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Comprehensive review of antimicrobial activities of plant flavonoids

Comprehensive review of antimicrobial activities of plant flavonoids Phytochem Rev (2019) 18:241–272 https://doi.org/10.1007/s11101-018-9591-z(0123456789().,-volV)(0123456789().,-volV) Comprehensive review of antimicrobial activities of plant flavonoids . . Ireneusz Go ´ rniak Rafał Bartoszewski Jarosław Kro ´ liczewski Received: 5 December 2017 / Accepted: 29 September 2018 / Published online: 6 October 2018 The Author(s) 2018 Abstract Flavonoids are one of the largest classes of ability to reverse the antibiotic resistance and enhance small molecular secondary metabolites produced in action of the current antibiotic drugs. Hence, the different parts of the plant. They display a wide range development and application of flavonoid-based drugs of pharmacological and beneficial health effects for could be a promising approach for antibiotic-resistant humans, which include, among others, antioxidative infections. This review aims to improve our under- activity, free radical scavenging capacity, coronary standing of the biological and molecular roles of plant heart disease prevention and antiatherosclerotic, hep- flavonoids, focusing mostly on their antimicrobial atoprotective, anti-inflammatory, and anticancer activities. activities. Hence, flavonoids are gaining high attention from the pharmaceutical and healthcare industries. Keywords Antibiotic resistance  Antibacterial Notably, plants synthesize flavonoids in response to mechanism  Medicinal plants  Nutraceuticals microbial infection, and these compounds have been Secondary metabolites found to be a potent antimicrobial agent against a wide range of pathogenic microorganisms in vitro. Antimi- Abbreviations crobial action of flavonoids results from their various AHL N-acyl homo-serine lactones biological activities, which may not seem very specific AGs Aminoglycoside antibiotics at first. There are, however, promising antibacterial CFU Colony-forming units flavonoids that are able not only to selectively target EC Epicatechin bacterial cells, but also to inhibit virulence factors, as ECG Epicatechin gallate well as other forms of microbial threats, e.g. biofilm EGCG Epigallocatechin gallate formation. Moreover, some plant flavonoids manifest EPI Efflux pump inhibitors FAS-I Fatty acid synthase type I FAS-II Fatty acid synthase type II I. Go´rniak FICI Fractional inhibitory concentration index Department of Biophysics, Faculty of Biotechnology, University of Wroclaw, Fryderyka Joliot-Curie 14a, MBC Minimum bactericidal concentration 50-383 Wroclaw, Poland MDR Multidrug resistant strains MIC Minimum inhibitory concentration R. Bartoszewski  J. Kroliczewski (&) MRSA Methicillin-resistant Staphylococcus aureus Department of Biology and Pharmaceutical Botany, Medical University of Gdansk, Hallera 107, MSSA Methicillin-sensitive Staphylococcus 80-416 Gdansk, Poland aureus e-mail: jakrol@windowslive.com 123 242 Phytochem Rev (2019) 18:241–272 phytochemicals that has been studied extensively for PMF Proton-motive force their antimicrobial properties are flavonoids (Pisteli ROS Reactive oxygen species and Giorgi 2012). Flavonoids, being mostly plants QS Quorum sensing pigments, belong to a wide class of chemical com- pounds (over 6000 different hydroxylated polyphe- nols) that carry out important functions in plants, including attracting insects that pollinate, combating Introduction environmental stresses such as microbial infection, and regulating the cell growth (Falcone Ferreyra et al. Pathogenic microorganisms have been a danger to the 2012; Kumar and Pandey 2013). Fruits and vegeta- human race since its genesis, being a major cause of bles are the main dietary sources of flavonoids for human morbidity and mortality. Until the discovery of humans. the first true antibiotic—penicillin—in 1928 and sulfa The flavonoids are known for their antioxidant, drugs in the 1930s, besides the toxic arsenic, the only anti-inflammatory, antiallergic, anticancer, antiviral, means of fighting infectious diseases were plant and antifungal properties (Harborne and Williams extracts of different sorts, though their usage yielded 2000; Havsteen 1983; Havsteen 2002). However, various results (Dar et al. 2016; Saleem et al. 2010; van since plants synthetize flavonoids in response to Miert 1994). microbial infection (Perumal Samy and Gopalakrish- Although, for the last 60 years, antibiotics played a nakone 2010), there is a growing interest about the major role in the treatment of infectious diseases antibacterial properties of flavonoids and their appli- caused by bacteria and fungi, the occurrence of cation in the therapy for human diseases. dangerous and antibiotic-resistant bacteria have been The therapeutic use of flavonoids is supported by observed to increase in frequency over the past several the successful use of preparations containing these decades. Drug resistance can be executed by multiple physiologically active constituents in folk medicine. mechanisms; hence overcoming such problem is not For example, Tagetes minuta containing querc- an easy task (Saleem et al. 2010). Reasons for the etagetin-7-arabinzylgalactoside was widely used in emerging antibiotic resistance include the irresponsi- the Argentinean folk medicine for the treatment of ble, unfit or too common use of antibiotics in fields, various infectious diseases (Tereschuk et al. 1997). such as medicine, veterinary, and especially in agri- Flower extracts of Retama raetam (Forssk) contain- culture (Pisteli and Giorgi 2012). Moreover, the ing, among others, licoflavone C and derrone dis- pipeline of new antimicrobial agents is running dry played antibacterial activity against Gram-positive since the 70 s, while the number of drug-resistant and Gram-negative bacteria (Edziri et al. 2012; Hayet bacteria has increased (Croft et al. 2007; Shah 2005), et al. 2008). Tripleurospermum disciforme (known by leading some to claim that a post-antibiotic era is the common name Mayweed), used as a disinfectant eminent (Appelbaum 2012). Hence, there is a pressing and in the treatment of some diseases in folk medicine need for finding new antimicrobial drugs. of Iran, contains abundance of flavonoids, including The use of plants as medicines has a long history in apigenin, kaempferol, luteolin, quercetin, and their the treatment of various diseases and to date, respective glycosides (Tofighi et al. 2015). * 100,000 plant species have been tested for their In this review, we have summarized the general medicinal use (Schmidt et al. 2012; Veeresham 2012). information about flavonoid structure, basic proper- In 2007 WHO estimated that 25% of available drugs ties, and their occurrence and discuss their scope of are derived from plants used in folk medicine (Cushnie antimicrobial activity as a possible replacement of et al. 2008). Besides the long-established clinical use, conventional antibiotics. Moreover, we have analyzed the plant-derived compounds display good tolerance the recently reported flavonoid compounds, which and acceptance among patients and seem like a display potent antimicrobial activities, and have credible source of antimicrobial compounds. Among provided examples of flavonoids that manifest syner- 109 new antibacterial drugs, approved in the period gistic and additive effects upon combining with other 1981–2006, 69% originated from natural products antibiotic drugs. (Newman 2008). One of the major groups of 123 Phytochem Rev (2019) 18:241–272 243 Flavonoids structure and nomenclature trivial names, along with semi-systematic and fully systematic names that follow the published IUPAC Flavonoids are a class of natural phenolic compounds recommendations (International Union of Pure and that include a C -C -C carbon framework (phenyl Applied Chemistry 1993). However, in this paper, we 6 3 6 benzopyran). The basic flavonoid structure consists of decided to use the most common approaches (trivial a 2-phenyl-benzo-c-pyrane nucleus comprising two and semi-systematic for well-known and novel benzene Rings A and B linked through a heterocyclic flavonoids, respectively), as we feel that they are pyran or pyrone Ring C. Depending on the level of sufficient for the purposes of this review. unsaturation and oxidation, flavonoids can be grouped into various subclasses, such as flavones (Fig. 1), isoflavones (Fig. 2), flavonols (Fig. 3), flavanols Physiological roles of plant flavonoids (otherwise known as catechins, Fig. 4), flavanones (Fig. 5), flavanonols (Fig. 6), chalcones and dihy- Flavonoids are present in most of the plants, generally drochalcones (Fig. 7), aurones and anthocyanidins in all of their organs. As the most abundant secondary (Fig. 8), and others that are not noted for their plant metabolites, their quantitative distribution varies antimicrobial activities (Falcone Ferreyra et al. from organ to organ or even plant to plant, depending 2012) and are not discussed in this paper. on the environment. The composition of flavonoids It should not be disregarded, that huge structural varies, depending on the plant’s water and nutrient diversity and wide biological activity of flavonoids availability, intensity of sunlight, type of soil, and the comes from their frequent modifications (Chen et al. age of the plant (Havsteen 2002). Nevertheless, plants 2018). Flavonoid glycosides, as well as their preny- of the same taxon tend to produce a similar set of lated, geranylated, methoxylated and hydroxylated flavonoids, suggesting that genetic predispositions of derivatives vary in structure and mode of antibacterial plants are dominant (Havsteen 2002; Nicotra et al. action (Cushnie and Lamb 2011). The chemical 2010). structures of flavonoids discussed here are presented Those compounds fulfill variety of functions in in Figs. 1, 2, 3, 4, 5, 7 and 8 (where these compounds plant organs. Anthocyanins along with other flavo- were grouped accordingly to their chemical classes). noids color flowers and fruits, which attracts pollina- Currently, three approaches are being used in tors and seed dispersers (reviewed in Narbona et al. naming flavonoid compounds, which may cause some 2014; Schiestl and Johnson 2013). In vegetative confusion, considering the huge number of new organs, anthocyanins and other non-pigmented flavo- flavonoids being isolated. The most common approach noids, such as flavones and flavonols, may provide is using the trivial name that relates to the subclass to some protective functions against many biotic and which the compound belongs to, or the plant from abiotic stressors like herbivores, UV radiation, cold, which it was first extracted from. Another approach is heat, drought, and salinity (Anderson et al. 2013; using the semi-systematic name, where the core of the Falcone Ferreyra et al. 2012; Hatier and Gould 2009). name comes from the subclass, for example, Moreover, flavonoids take part in energy transfers, 0 0 3,5,7,3 ,4 -pentahydroxyflavone. The third method is regulation of photosynthesis and morphogenesis, naming the flavonoids by their systematic chemical regulation of growth factors, and sex determination names, for example, 3,4-dihydro-2-phenyl-2H-1-ben- (Harborne and Baxter 1999). zopyran (flavan). Although this method is overcom- More importantly, there are reports suggesting that plicated in case of common flavonoids, it is the most flavonoids are important antimicrobials in plant life. precise approach, and thus superior to other naming To arrest the spread of pathogens, plants possess an approaches, especially when naming novel com- innate immunity that involves different layers of pounds (Cushnie and Lamb 2005). One of the defense responses and some of these defenses include recommendations for the flavonoid nomenclature biosynthesis of flavonoids (Piasecka et al. 2015). Beck was prepared by the IUPAC (Rauter 2013). These and Stengel (2016) found that flavonoids are mostly recommendations establish rules for the general concentrated along the vascular strands of leaves, nomenclature of flavonoids, providing examples of rather than being evenly distributed throughout the acceptable trivial names, and names derived from leaf tissue. This is due to the need for the quick 123 244 Phytochem Rev (2019) 18:241–272 Fig. 1 Chemical structures of flavones distribution of flavonoids via vascular strands, which feeding, and possibly pathogen attack response. In shows the important roles of flavonoids in physiolog- fact, flavonoids serve as phytoalexins categorized as ical regulation, chemical messaging, deterring of the compounds that protect plants from different types of 123 Phytochem Rev (2019) 18:241–272 245 Fig. 2 Chemical structures of isoflavones pathogens (Cowan 1999). For example, a flavanone Membrane disruption sakuranetin was found in abundance in rice, where it combats various pathogens, both bacterial and fungal The bacterial plasma membrane is responsible for (Cho and Lee 2015). Moreover, many classes of osmoregulation, respiration and transport processes, flavonoids have been identified as allelochemicals that biosynthesis and cross-linking of peptidoglycan, as inhibit the growth of microorganisms around the plant. well as biosynthesis of lipids. For performing all of these functions, membrane integrity is a prerequisite, Examples of those include chalcones, dihydrochal- cones, flavonols, flavanols, flavanones and isoflavo- and its disruption can directly or indirectly cause metabolic dysfunction and finally lead to bacterial noids (Beck and Stengel 2016; Iwashina 2003). death (Hartmann et al. 2010). To date, flavonoids, especially catechins, have been widely studied for Mechanisms of antimicrobial action by flavonoids their antimicrobial properties in both Gram-positive and Gram-negative bacteria. The interactions of To date, many flavonoids were characterized by the flavonoids with lipid bilayers involve two mechanisms antibacterial activities against plant pathogens, which (Tsuchiya 2015). The first is associated with the could be effectively applied to fight human pathogens. partition of the more non-polar compounds in the Moreover, the antibacterial activities of many plant- hydrophobic interior of the membrane, while the second one includes the formation of hydrogen bonds derived flavonoids use different mechanisms than those of conventional drugs, and thus could be of between the polar head groups of lipids and the more hydrophilic flavonoids at the membrane interface. importance in the enhancement of antibacterial ther- apy (Pandey and Kumar 2013). Moreover, nonspecific interactions of flavonoids with 123 246 Phytochem Rev (2019) 18:241–272 Fig. 3 Chemical structures of flavonols phospholipids can induce structural changes in the influence pharmacological properties of flavonoids properties of the membrane (e.g., thickness and themselves (Arora et al. 2000). However, the mech- fluctuations) and indirectly modulate the distribu- anism responsible for the flavonoid–membrane inter- tion/function of membrane proteins, as well as action has not yet been fully understood and the 123 Phytochem Rev (2019) 18:241–272 247 Fig. 4 Chemical structures of flavanols (catechins) literature so far remains controversial (Sanver et al. rupture the bacterial membrane by binding to the lipid 2016). bilayer and by inactivating or inhibiting the synthesis Catechins (Fig. 4) are often linked to the antimi- of intracellular and extracellular enzymes (Reygaert crobial effects and related to the interactions with the 2014). Moreover, recent studies employing cell mod- cell membrane. Contrasting to the protective effects of els have highlighted the pro-oxidative activity of flavonoids on membranes, catechins were shown to several polyphenols already known as antioxidants, 123 248 Phytochem Rev (2019) 18:241–272 Fig. 5 Chemical structures of flavanones namely epicatechin (EC, compound 39), epigallocat- burst by the generation of reactive oxygen species echin gallate (EGCG, compound 42) and a flavonol (ROS) that cause alteration in the membrane perme- quercetin (32) (Bouayed and Bohn 2010). Fathima and ability and membrane damage. It should be noted Rao (2016) reported that the mode of action of killing however, that oxidative bursts occur only at high bacteria by catechins was found to be an oxidative EGCG concentrations. Liposome studies also showed 123 Phytochem Rev (2019) 18:241–272 249 Fig. 6 Chemical structures of flavanonols membrane disruption by this compound (Sirk et al. increased activities are the result of enhanced mem- 2009). Interestingly, liposomes containing high brane affinity of their long acyl chains (Matsumoto amounts of negatively charged lipids, were less et al. 2012). susceptible to catechin damage, just as catechins have Other flavonoids are also often reported to possess less effect on Gram-negative bacteria due to nega- membrane-disrupting activities. Sato et al. (1997) 0 0 tively charged LPS of the outer bacterial membrane reported that 2,4,6 -trihydroxy-3 -methylchalcone (Ikigai et al. 1993). It correlates well with studies (62) leads Streptococcus mutans to leak intracellular reporting lower antibacterial activities of catechins substances such as protein and ions. Mirzoeva et al. against Gram-negative bacteria versus Gram-positive (1997) noticed that quercetin (32) from propolis bacteria (Cushnie et al. 2008). Cushnie et al. (2008) causes a decrease of proton-motive force in S. aureus reported that membrane disruption by catechins and suggested that increased membrane permeability causes potassium leakage in methicillin-resistant Sta- contributes to the synergistic activity of propolis with phylococcus aureus (MRSA) strain, which is the first antibiotics, such as tetracycline and ampicillin (Ste- indication of a membrane damage in microorganisms panovic et al. 2003). Furthermore, Ollila et al. (2002) (Lambert and Hammond 1973). They have also showed that flavones acacetin (9) and apigenin (10), as noticed that more lipophilic, acylated to 3-O-oc- well as flavonols morin (26) and rhamnetin (37), tanoyl-epicatechin (43) yields better results in antibac- caused destabilization of the membrane structure by terial studies, than unmodified epicatechin (39). The disordering and disorientation of the membrane lipids 123 250 Phytochem Rev (2019) 18:241–272 Fig. 7 Chemical structures of chalcones. It should be noted that nomenclature of chalcones in this paper, according to the most positions of substituents in semi-systematic names may differ common numeration approach (Boumendjel 2003). The chem- compared to original reports due to variations in numeration of ical structures are consistent with the original reports the positions of the rings in chalcone structures. We adjusted the and induced leakage from the vesicle. Tsuchiya and at the C-3 position of C Ring) were found to be highly Iinuma (2000) reported that flavanones naringenin active against S. aureus, Staphylococcus epidermidis, (51) and sophoraflavanone G (56) have antibacterial and Enterococcus faecalis due to flavonoid-initiated activity against MRSA. They have also noticed that bacterial cell aggregation that influences the integrity the antibacterial effect of these flavonoids is caused by of membranes and causes biofilm disturbance reducing the fluidity in hydrophilic and hydrophobic (Budzynska et al. 2011). regions of the both inner and outer cellular membrane. Concluding, differences in the number and distri- Sanver et al. (2016) showed that flavonols quercetin bution of hydroxyl groups, the polymerization degree, (32), rutin (quercetin-3-O-rhamnoglucoside, com- as well as the presence of a methoxy groups in the C pound 35) and tiliroside (38) decreased the bilayer ring, can influence the type of interactions that occur thickness, furthermore rutin disrupted the lipid mono- between different flavonoids and lipid bilayers (Oteiza layer structure. Synthetic lipophilic 3-arylidenefla- et al. 2005). Moreover, flavonoids lacking hydroxyl vanones (substituted with various phenolic compound groups on their B Rings are more active against 123 Phytochem Rev (2019) 18:241–272 251 cells to a surface, which is followed by cells dividing and developing into mature, three-dimensional bio- films (Costerton et al. 1995). However, Kragh et al. (2016) have showed that multi cellular bacteria composites perform better than single cells during the biofilm development. Interestingly, there are reports of flavonoids supporting bacterial aggregation. Stapleton et al. (2004) observed pseudo multicellular aggregates of S. aureus after incubation with EGCG (42) and 3-O-octanoyl-epicatechin (43). Flavonols have also been reported to cause aggregations of bacterial cells, particularly galangin (25) (Cushnie Fig. 8 Chemical structures of other flavonoids mentioned in et al. 2007). It should be noted however, that growth of this paper the bacteria was inhibited after aggregation. Presum- ably, flavonoids cause bacterial aggregation by their microbial membranes than those with the –OH groups partial lysis, which leads to membrane fusion, and (Chabot et al. 1992). This is due to negative correlation consequently reduces the active nutrient uptake via a between the relative hydrophobicity of flavonoids and smaller membrane area, thus it cannot be stated that the number of hydroxyl group present. Furthermore, flavonoids support biofilm formation. On the contrary, other authors suggest that lipophilic flavonoids which multiple research teams reported that flavonoids in are highly hydroxylated can be more disruptive for fact inhibit biofilms. For example, Awolola et al. membrane structure (Matijasˇevic´ et al. 2016; Mishra (2014) showed a significant antibiofilm activity of et al. 2009; Sato et al. 1996). It is worth noting that isovitexin (apigenin-6-C-glycoside 14), EC (39) and bacterial membrane damage by catechins and other 5,7,4 -trihydroxyflavanol (44) against S. aureus ATCC flavonoids may also result in an inability of the 29213. Similarly, El-Adawi (2012) observed a bacteria to secrete toxins (Lee et al. 2011; Shah et al. 55–66% decrease in S. mutans biofilm formation upon 2008). exposure to 2–15% EC. However, Nyila et al. (2012) observed that EC from Acacia karroo did not reduce Biofilm formation Listeria monocytogenes biofilms. Quorum sensing, in particular, autoinducer-2-me- Bacterial biofilm-based infections constitute a signif- diated cell–cell signaling, was proposed as a signifi- icant amount of all microbial and chronic infections in cant regulatory factor for the biofilm production in animals and humans, as well as in food spoilage Escherichia coli, Vibrio spp., and Salmonella typhi- (Abdullahi et al. 2016; Jamal et al. 2018). One of the murium (Vikram et al. 2010). Interestingly, citrus crucial features of bacteria growing as biofilms is that flavonoids, such as apigenin (10), kaempferol (28), they become from 10 to 1000 times more resistant to quercetin (32) and naringenin (51) are effective antimicrobial agents when compared to their plank- antagonists of cell–cell signaling (Vikram et al. tonic cells (Kon and Rai 2016). The current medicinal 2010). Furthermore, quercetin (assigned with approaches to eradicate biofilm bacteria using sys- antileishmanial and antibacterial activities (Gatto temic antibiotic treatments are very limited. However, et al. 2002; Prasad et al. 2014)) was shown to inhibit antibiofilm phytochemical compounds were shown to enteroaggregative E. coli EAEC 042 biofilm (Barboza influence the bacterial biofilm establishment and et al. 2016). Quercetin inhibited alginate production in growth as well as the related bacterial adhesion, a concentration-dependent manner, resulting in the motility, and quorum sensing (QS). Furthermore, declination in the adherence during biofilm formation. these compounds are believed to have a lower Moreover, this flavonoid inhibited N-acyl homoserine probability of bacterial resistance occurrence (Borges lactones (AHL)-mediated QS. Most notably, quercetin et al. 2013). upregulates the expression of several iron siderophore Although the initiation of biofilm formation has 3? proteins limiting the amount of Fe that is required been thought to be due to random attachment of single for the biofilm formation of Pseudomonas aeruginosa 123 252 Phytochem Rev (2019) 18:241–272 (Ouyang et al. 2016; Symeonidis and Marangos 2012). Shiga toxin 2 stx2). However, phloretin was also Kaempferol (28), epicatechin gallate (ECG, com- shown to induce stress resistance genes, such as pound 40) and EGCG (42) were reported to mediate marRAB and hcsBA genes (Lee et al. 2011). Thus, the displacement of AHL molecules from LuxR-type phloretin could positively influence the antibiotic transcriptional activator protein (Roy et al. 2017), resistance as well. while chrysin (12), phloretin (68) and naringenin (51) Efflux-pump inhibitors (EPI) are aimed not only to inhibited QS synthase/receptor pairs, LasI/R, and block the efflux pumps, but also the biofilm formation RhlI/R (Paczkowski et al. 2017). Cranberry A-type (Sana et al. 2015). Pinostrobin (a dietary flavanone proanthocyanidins (Fig. 8) are also found to be anti- discovered in the wood of pine, Pinus strobus, adhesion agents against the Gram-negative bacterium compound 53) enhanced membrane permeability in P. aeruginosa (Ulrey et al. 2014). Ulrey et al. (2014) both Gram-positive and Gram-negative bacteria (E. suggested that the mechanism of A-type proantho- faecalis, S. aureus, E. coli and P. aeruginosa), which cyanidins against the biofilm formation results from correlated well with its effect on EPI and antibiofilm their chelating properties. formation in Gram-negative bacteria (Christena et al. Hydrophilic flavonoids can interact at the mem- 2015). Christena et al. (2015) suggested that pinos- brane surface and provide protective actions against trobin exerts its antibiofilm effect by the mechanism different deleterious agents and biofilm formation that is unrelated to its EPI effect and may not involve (Oteiza et al. 2005). However, Lee et al. (2011) the repression of curli genes. This is in contrast to the showed that biofilm reduction by flavonoids does not report of pinostrobin EPI effect in S. typhimurium result from their antioxidant properties alone. They (Baugh et al. 2012). Tea EGCG (42) provides another demonstrated that flavones, such as 6-aminoflavone example of effective antimicrobial agent against both (1), 6-hydroxyflavone (2), apigenin, chrysin (12), as the planktonic and biofilm forms of E. faecalis. Tea well as isoflavones daidzein (21) and genistein (22), EGCG inhibits not only the bacterial growth, but also and a dihydrochalcone phloretin (68) had inhibitory suppresses the expression of specific genes related to effects on E. coli O157:H7 biofilm formation, biofilm formation (Lee and Tan 2015). A number of although antioxidant compounds (vitamin C and prenylated flavonoids isolated from Epimedium spe- vitamin E) did not show such effect. Furthermore, cies inhibited Porphyromonas gingivalis biofilm for- phloretin (a natural, nontoxic apple flavonoid) caused mation, however, the antibiofilm mechanism of those the most significant reduction of enterohemor- flavonoids remains unknown (Kariu et al. 2016; rhagic E. coli O157:H7 biofilms without affecting Olczak et al. 2005). the growth of planktonic cells. Similar effect was showed for the auronol called derriobtusone A (74) Inhibition of cell envelope synthesis that inhibited the biofilm formation in E. coli, although the planktonic growth of E. coli was only weakly Bacterial-type II fatty acid synthase (FAS-II) differs in inhibited (Vasconcelos et al. 2014). Notably, phloretin many ways from the mammalian one (FAS-I), which (68) showed a dose-dependent inhibition of biofilm makes it excellent target for an antimicrobial agent. and did not harm commensal E. coli K-12 and Multiple inhibitors of the FAS-II components have nonpathogenic E. coli ATCC 4157 biofilm (Lee been reported to date and summarized below. et al. 2011). This is an important feature of phloretin, Quercetin (32), apigenin (10), and sakuranetin (54) since antibiofilm agent should be able to selectively were shown to inhibit 3-hydroxyacyl-ACP dehydrase inhibit the pathogenic strains without wiping out the from Helicobacter pylori (Zhang et al. 2008b). commensal microflora. Extensive research has been made on 3-ketoacyl- Fimbriae, including curli and pili, are important ACP synthase from E. faecalis and 11 flavanones with factors for the biofilm formation (Rendo´n et al. 2007). different configurations of hydroxyl groups have been Phloretin (68) reduced fimbriae formation in E. coli screened (Jeong et al. 2009). The best result was O157:H7, due to repression of the expression of the obtained for the use of eriodictyol (49), naringenin curli genes (csgA and csgB) (Lee et al. 2011). This (51) and taxifolin (60). Parallel docking studies, study also reported that phloretin repressed the conducted by the same team, indicate that hydrogen expression of two toxin genes (hemolysin hlyE and bonds between flavonoid hydroxyl groups at C-4 and 123 Phytochem Rev (2019) 18:241–272 253 C-5 of B ring and enzyme amino acid residues Arg38 from Scutellaria baicalensis, 11) supported induced and Phe308 were the key for their antibacterial activity by EGCG (42) peptidoglycan damage (Fujita et al. 0 0 (Figs. 5, 6). Elmasri et al. (2017) reported 5,6,7,4 ,5 - 2005). Flavonols galangin (25), kaempferide (30), and pentahydroxyflavone (3) and 5-hydroxy-4 ,7- kaempferide-3-O-glucoside (31) showed not only dimethoxyflavone (5) to downregulate the malonyl activity against amoxicillin-resistant E. coli, but also CoA-acyl carrier protein transacylase fabD (MCATs) the ability to reverse the resistance via inhibition of that regulates bacterial FAS-II. Thus, these two peptidoglycan and ribosome synthesis (Eumkeb et al. flavones are considered to be the promising drugs for 2012). Another study on the mechanism of action of blocking the bacterial growth. Furthermore, EGCG catechins showed that they interfere with the biosyn- (42) from green tea inhibited specific reductases thesis of the bacterial cell wall by binding with the (FabG, FabI) in the bacterial FAS-II (Zhang and Rock peptidoglycan layer. Cell wall synthesis was also 2004). FabG enzyme (beta-ketoacyl-[acyl carrier inhibited by a synergistic effect of EGCG (42) and protein] reductase) participates in the fatty acid DL-cycloserine (an inhibitor unrelated to penicillin- biosynthesis and is the only known isoenzyme to binding protein) (Zhao et al. 2001). Furthermore, since catalyze the reduction of the bacterial membrane b- both EGCG and b-lactams (benzylpenicillin, oxacil- keto groups (Li et al. 2006). Therefore, this enzyme is lin, methicillin, ampicillin, and cephalexin) directly or an ideal target for the development of new antibiotics. indirectly target peptidoglycan (Zhao et al. 2001), Inactivation of FabG probably occurs as a result of EGCG synergizes the activity of b-lactams. Kinetic EGCG-induced aggregation of this enzyme. Finally, studies on D-alanine-D-alanine ligase, responsible for other enzymes involved in fatty acid biosynthesis, the production of the terminal dipeptide of peptido- such as 3-ketoacyl-ACP reductase and enoyl-ACP glycan precursor UDPMurNAc-pentapeptide, showed reductase from many bacteria are inhibited by EGCG that quercetin (32) and apigenin (10) inhibit this as well (Li et al. 2006; Zhang et al. 2008a; Zhang and enzyme (Wu et al. 2008). These two flavonoids bind to Rock 2004). the active center of D-alanine-D-alanine ligase (Singh Mycobacteria cause some of the most serious et al. 2013; Wu et al. 2008). However, quercetin had diseases, which are notoriously difficult to treat (Chen poorer activity compared to apigenin, which is et al. 2010). The presence of mycolic acids is one of attributed to its additional -OH groups that enforce the most distinctive and essential survival features of its affinity to the enzyme (Figs. 1, 3). In the contrast, the mycobacterial cell wall. Those bacteria possess sakuranetin (54), a flavonoid similar to apigenin (it has two types of fatty acid synthases, a mammalian-type 7-methoxy instead of 7-hydroxy group, and no double FAS-I, and a bacterial-type FAS-II, both of which are bond on C ring, Figs. 1, 5), has no inhibitory effect important for the biosynthesis of mycolic acid. A (Wu et al. 2008). Furthermore, the hydrophilic nature number of flavonols have been shown to inhibit FAS-I, of quercetin limits its penetration into the bacterial including: quercetin (32), kaempferol (28), fisetin cell. (24), morin (26) and myricetin (27), as well as flavones baicalein (11) and luteolin (15), and EGCG (42) (Li Inhibition of nucleic acid synthesis and Tian 2004). Moreover, some of these flavonoids possessed activity against FAS-II components as well, Flavonoids have been reported to be significant including enoyl-ACP-reductase, b-ketoacyl-ACP topoisomerases inhibitors, which contributes to their reductase, and b-hydroxyacyl-ACP dehydratases antimicrobial activity. For example, DNA gyrase is an (Brown et al. 2007). Furthermore, Brown et al. essential enzyme for the DNA replication and it is 0 0 (2007) reported that chalcones 4,2 ,4 -trihydroxychal- exclusive to prokaryotes, which makes it an attractive cone (61), butein (64), isoliquirtigenin (65), and a target for antibacterial drugs (Plaper et al. 2003). flavonol fisetin (24) possess inhibitory activity against Ohemeng et al. (1993) reported the inhibition of DNA FAS-II from Mycobacterium bovis BCG. gyrase from E. coli by quercetin (32), apigenin (10), 0 0 Peptidoglycan is an essential component of the and 3,6,7,3 ,4 -pentahydroxyflavone (4). Moreover, in bacterial cell wall, and the inhibition of its synthesis is silico analysis suggested that subunit B of DNA gyrase a common mechanism of action of conventional from Mycobacterium smegmatis and M. tuberculosis antimicrobial drugs and flavonoids. Baicalein (flavone can be targeted by quercetin (Suriyanarayanan et al. 123 254 Phytochem Rev (2019) 18:241–272 2013). This report was confirmed, by the studies nucleic acid binding capacity, have been screened as conducted on different gyrase subunits that revealed helicase inhibitors. A flavone luteolin (15) and its quercetin binding to the B subunit of gyrase and the structurally related flavonols, such as morin (26) corresponding blockage of ATP binding pocket by the myricetin (27), were shown to inhibit the replicative formation of hydrogen bonds via 5, 7 and 3 –OH helicases like DnaB and RecBCD helicase/nuclease of groups to the amino acid residues of DNA gyrase E. coli (Xu et al. 2001). Moreover, myricetin inhibited (Fig. 3) (Plaper et al. 2003). It is in correlation with the Gram-negative bacterial growth and was proposed to studies that reported the blockage of ATP binding be a potent inhibitor of numerous DNA and RNA pocket of D-alanine-D-alanine ligase by the same polymerases, as well as viral reverse transcriptases flavonoids (Wu et al. 2008). Moreover, the related (along with baicalein (11)) (Ono et al. 1990) and flavonoids chrysin (12) and kaempferol (28) greatly telomerases (Griep et al. 2007). inhibited DNA gyrase from E. coli (nobiletin (16), Dihydrofolate reductase (DHFR) is a common tangeritin (19) and myricetin (27) were less efficient target of many drugs, including antimicrobial agents. inhibitors) (Wu et al. 2013). Those studies showed that The DHFR is an important enzyme of the folic acid flavonoid hydroxyl groups allow better association synthesis pathway, which provides precursor of with the gyrase compared to methoxy groups, pyrimidines and purines (Bhosle and Chandra 2016). although an extra 5 -OH in myricetin greatly EGCG (42) was reported to inhibit DHFRs from decreased its gyrase inhibition properties (Fig. 3) Streptomonas maltophilia, Mycobacterium tuberculo- (Wu et al. 2013). The second mechanism of DNA sis, and E. coli (Navarro-Martinez et al. 2005; Raju gyrase inhibition was proposed by molecular docking et al. 2015; Spina et al. 2008). Furthermore, EGCG studies (Fang et al. 2016; Plaper et al. 2003), which had synergistic effects with other inhibitors of folic suggest that flavonoids inhibit the DNA supercoiling acid pathway, such as sulfamethoxazole and etham- by competitively interacting with the ATP binding site butol (Navarro-Martinez et al. 2005; Raju et al. 2015). of the DNA gyrase B subunit (GyrB). In this mech- Flavonoid DNA intercalation, that inhibits bacterial anism of action, flavonoids binding to DNA stabilizes nucleic acid synthesis, was also proposed as a the DNA–gyrase complex that leads to DNA cleavage mechanism underlying their antimicrobial properties. induction (Plaper et al. 2003). Moreover, Fang et al. Mori et al. (1987) noticed that the incubation with (2016) reported 3-hydroxyl, 5-hydroxyl, 7-hydroxyl, EGCG (42), myricetin (27), and robinetin (17) resulted and 4-carbonyl groups to be crucially active sub- in reduced DNA, RNA, and protein synthesis by stituents of flavonoids by interacting with key residues Proteus vulgaris and S. aureus. They proposed that of GyrB. This result is in accordance with previous this process resulted from the intercalation of studies of Wu et al. (2013). Furthermore, Ulanowska flavonoids with nucleic acids, mediated by flavo- 0 0 0 et al. (2006) showed that isoflavone genistein (22) noid-free hydroxyl group at C-3 of A ring and 3 ,4 ,5 - inhibits the growth of Vibrio harveyi (with interme- trihydroxyl motif at B ring (Figs. 1, 3, 4). However, diate effect on Bacillus subtilis and little effect on DHFR inhibition could explain the reduction of DNA E. coli) in a dose–response manner. They suggested and RNA synthesis by EGCG, as well. Furthermore, that the inhibition of growth of the bacteria species myricetin and robinetin, which share similar structure, results from genistein-mediated stabilization of the also seem to be the possible DHFR inhibitors. These topoisomerase II–DNA cleavage complex that leads to observations raise the question, ‘‘whether those com- the impairment of cell division and/or completion of pounds only reduce nucleic acid synthesis via DNA chromosome replication (Verdrengh et al. 2004). intercalation/DHFR inhibition or they have got mul- Helicases are ubiquitous motor proteins that sepa- tiple target sites?’’ Giving the low specificity of rate and/or rearrange nucleic acid duplexes in reac- EGCG, lowered DNA and RNA synthesis could result tions fueled by adenosine triphosphate (ATP) from multiple enzyme inhibitions and proton-motive hydrolysis (Shadrick et al. 2013). Similarly to topoi- force (PMF) disruption. Numerous studies reported on somerases and gyrases, their function is essential for flavonoid-mediated topoisomerase inhibition and DNA replication. Recent studies suggested these DNA intercalation in human cancer cells (reviewed proteins as molecular targets of flavonoids. Flavones by Russo et al. (2012)), suggesting the universal and flavonols, the groups of pharmacophores with mechanisms of their action. 123 Phytochem Rev (2019) 18:241–272 255 Inhibition of electron transport chain and ATP silibinin (58) and silymarin (59) (Chinnam et al. synthesis 2010). Furthermore, quercetin (32), quercetin-3-glu- coside (isoquercetin, 33) and quercetin-3-O-rham- The membrane potential, being the essential main noside (quercitrin, 34) are known to prevent the ATP energy source for almost all chemical processes in hydrolysis, although not the ATP synthesis (Chinnam living systems, is the most important factor for the et al. 2010). EGCG (42) inhibited the acidogenic and survival and growth of bacterial cells. Notably, the aciduric properties of S. mutans, probably by the treatment of S. aureus with isobavachalcone (66) and inhibition of the enzymatic activity of F F ATPase 1 O 6-prenylapigenin (7) from Dorstenia species resulted (Xu et al. 2011, 2012). Ulrey et al. (2014) demon- in bacterial membrane depolarization (Dzoyem et al. strated that the treatment of P. aeruginosa with A-type 2013). Furthermore, Haraguchi et al. (1998) reported proanthocyanidins (isolated from Cranberries, mono- that licochalcones from Glycyrrhiza inflata inhibited mer shown on Fig. 8—compound 73) downregulated oxygen consumption in Micrococcus luteus cells, and the proteins involved in ATP synthesis: a cytochrome the site of inhibition was thought to be between CoQ c (NP_251172), hypothetical protein (NP_251171); as and cytochrome c in the bacterial electron transport well as protein subunits of acetyl-CoA carboxylase chain. Although licochalcones A, B, C, and D (NP_254123), fumarase (NP_253023), and aconitate (compounds 69–72) caused inhibition of NADH- hydratase (NP_249485). cytochrome c reductase activity in the membrane A decline in the overall bacterial metabolism can fraction, while cytochrome c oxidase was not inhib- lead to the indirect arrest of the biofilm formation, as 0 0 ited. However, only licochalcones A and C manifested well. Notably, the 4 ,5 ,5-trihydroxy-6,7-dimethoxy- antibacterial activities against Gram-positive bacteria flavone (8) (from Teucrium polium) was reported to and it was attributed to the presence of lipophilic affect the F-type ATP synthase (atpD) and thus reduce prenyl moiety on the D ring of licochalcones A and C the ATP availability in S. aureus (Elmasri et al. 2017). (Fig. 7), which facilitates their infiltration into the bacterial cell (Haraguchi et al. 1998). Antibacterial action of flavonoid-metal complexes Recently, it has been reported that flavonoids can inhibit F F ATPase of E. coli (Chinnam et al. 2010). Havsteen (2002), in his voluminous paper on flavo- 1 O ATP synthase is a highly conserved enzyme with two noid properties, tried to explain the antibacterial sectors, F and F .In E. coli,F is composed of activities of flavonoids. Since many studies showed 1 O 1 a3b3cdeab2c10, while F consists of ab2c10. ATP the ability of flavonoids to chelate transition metal ions hydrolysis and synthesis occur on three catalytic sites (Karlı´cˇkova´ et al. 2015; Li et al. 2015; Riha et al. 2014; in the F sector, whereas proton movement occurs Samsonowicz et al. 2017), he pointed out that many through the membrane-embedded F (Senior et al. flavonoids could cause the inhibition of bacterial metal 2002). A wide range of polyphenols has been shown to enzymes. This mechanism of action is common for bind at the distinct polyphenol binding site and inhibit many other antibacterial substances, including lacto- the ATP synthase. The polyphenol binding pocket lies ferrin from human milk. at the interface of a, b, and c-subunits of F sector. Flavonoid chelation sites include two proximal Therefore, the proposed mode of flavonoid inhibitory hydroxyl groups (o-dihydroxyl group in ring B or ring action was the binding at the polyphenol binding A), the 3-hydroxy-4-keto group of the C ring or via the pocket of ATP synthase and the blockage of clockwise 5-hydroxy-4-keto position of the A and C rings. or anticlockwise rotation of the c-subunit (Gledhill Although the antibacterial activity of complexes et al. 2007). Furthermore, the polyphenol binding depends strongly on the metal ion, the preferred metal pocket residues are highly conserved among different binding site depends on the flavonoid, and on the pH species including human, bovine, rat, and E. coli value (Kasprzak et al. 2015). Literature data suggested (Walker et al. 2000) Thus, there is great chance that that the flavonoids predominantly form complexes other microorganisms may be susceptible to this type with a metal in 1:2 ratio and that their binding of inhibition (Chinnam et al. 2010). The most effective efficiency is also associated with the transition state of 2? 3? inhibitors of E. coli F F ATPase include baicalein metal ions (e.g., Fe [ Fe ) (Ren et al. 2008). One 1 O (11), morin (26), EC (39), as well as flavanonols of the well-known flavonoid–metal complexes are the 123 256 Phytochem Rev (2019) 18:241–272 quercetin (32) complexes. Bravo and Anacona (2001) Flavonoids, especially catechins and proantho- 2? 2? 2? 2? demonstrated that Mn ,Hg ,Co , and Cd cyanidins (due to antioxidant properties), were pro- complexes of quercetin show bactericidal effect posed to neutralize bacterial toxic factors originating against S. aureus, Bacillus cereus, P. aeruginosa, from Vibrio cholerae, S. aureus, Vibrio vulnificus, E. coli, and Klebsiella pneumoniae. Comparatively, Bacillus anthracis, and Clostridium botulinum quercetin alone at the same concentration had no (Ahmed et al. 2016; Choi et al. 2007; Delehanty activity. Similar reports are available for morin (26, et al. 2007). Similarly, genistein (22) inhibited the 2? 2? Mg and Ca complexes) against Micrococcus exotoxin from S. aureus, while kaempferol (28), flavus and S. aureus (Panhwar and Memon 2011) kaempferol-3-O-rutinoside (29), and quercetin gly- 2? 2? 2? and 4 ,7-dimethylapigenin (6, Cu ,Ni ,Co , coside inhibited the neurotoxin from C. botulinum 2? 3? 3? 2? 2? Zn ,Fe ,Cr ,Cd , and Mn ) against E. coli, (Sawamura et al. 2002). The a-hemolysin (Hla), a S. aureus, and P. vulgaris (Wang et al. 1992). Despite member of bacterial pore-forming b-barrel toxins, is these studies, the antibacterial mechanism of flavo- one of the most important virulence factors produced noid–metal complexes have not been conclusively by S. aureus. Soromou et al. (2013) reported that 3? 3? established yet. For example, the La and Gd (their pinocembrin (52), a honey flavanone, reduced S. metal–ligand ratio was 6:3, and 8:3, respectively) aureus a-hemolysin production in a concentration- complexes of morin (26) had lesser antibacterial dependent manner (pinocembrin reduces the tran- activity, when compared to their parent flavonoids scription level of Hla and d-haemolysin genes). (Kopacz et al. 2005). Complexation with metal ions Pinocembrin have also been studied to evaluate its causes changes in the flavonoid structure, in their mechanism of actions on the bacterial membranes of affinities to various intracellular targets, as well as in Neisseria gonorrhoeae. Although the pinocembrin- their antioxidant and prooxidant properties. Hence, the induced cell lysis has been observed in the study, different antibacterial activities of the flavonoid–metal mechanisms of actions of this compound have not ion complexes result from their interaction with been fully elucidated (Rasul et al. 2013; Ruddock et al. different targets than their parent flavonoids. By all 2011). Sugita-Konishi et al. (1999) reported that means, an antimicrobial resistance to metals (reviewed EGCG (42) and gallocatechin gallate (GCG, 41) by Hobman and Crossman (2015)) cannot be suppressed the release of verotoxin from enterohem- excluded. orrhagic E. coli cells and concluded that green tea catechins can be used to prevent the food poisoning Inhibition of bacterial toxins caused by E. coli. In conclusion, flavonoids manifest many interesting Important virulence factors, such as bacterial hyalur- mechanisms of antibacterial action (Fig. 9). There are onidases (produced by both Gram-positive and Gram- however, antibacterial flavonoids with little known negative bacteria), directly interact with host tissues or mechanism, as well as the ones with multiple cellular mask the bacterial surface from host s defense mech- targets. Further investigation of action mechanisms anisms. In the bacterial pathogenesis, hyaluronidase- and structure–activity relationship could help us not mediated degradation of hyaluronan increases the only to reveal novel antimicrobials, but also to find the permeability of connective tissues and decreases the most target-specific ones, which in case of possible viscosity of body fluids (Girish and Kemparaju 2007). therapeutic application of flavonoids, remains critical. Notably, flavonols, such as myricetin (27) and quercetin (32) have been identified as hyaluronic acid lyase (Hyal B) inhibitors in Streptococcus agalactiae. Flavonoids as antimicrobial potentiators The inhibitory effect of the flavonoids increased with the number of hydroxyl groups present in the Mechanism of resistance to antibacterial agents flavonoid structure (Hertel et al. 2006). However, hyaluronate lyases from Streptomyces hyalurolyticus Pathogenic bacteria may gain the resistance to antibi- (Hyal S), and Streptococcus equisimilis (Hyal C) were otic drugs through different mechanisms, such as only inhibited slightly (Hertel et al. 2006). prevention of interaction of the drug with the target, efflux of the antibiotic from the cell, and direct 123 Phytochem Rev (2019) 18:241–272 257 Fig. 9 Diagrammatic representation of action mechanism of which involves inhibition fatty acid synthase (FAS—5) and flavonoids. Flavonoids can kill or inhibit bacterial cells in peptidoglycan synthesis (7a—inhibition of Ala–Ala dipeptide variety of ways, such as causing membrane disruption (1) and synthesis, 7b—inhibition of peptidoglycan cross-linking). inhibition of nucleic acid synthesis (2a—inhibition of dihydro- Flavonoids can inhibit efflux pumps as well, which can lead to folate reductase (DHFR), 2b—helicase inhibition, 2c—gy- reversing antimicrobial resistance (6). Moreover inhibition of rase/topoisomerase inhibition), as well as inhibit bacterial NADH-cytochrome c reductase activity in the bacterial virulence, e.g. toxins (3) and quorum sensing, which impairs respiratory chain (8) and inhibition of ATP synthase (9) were their ability to form biofilms (4). Antimicrobial action can be also reported also executed through inhibition of cell envelope synthesis, destruction or modification of the drug compound Arias 2016). The aminoglycoside-modifying enzymes (Fig. 10). Moreover, bacteria can share the resistance (AMEs) that covalently modify the hydroxyl or amino genes, for example, the gene of b-lactamase, an groups of the aminoglycoside molecule become the enzyme hydrolyzing the amide bond in the b-lactam predominant mechanism of aminoglycoside resistance ring through transformation (incorporation of naked worldwide (Ramirez and Tolmasky 2010). Further- DNA), transduction (phage-mediated), and conjuga- more, the chloramphenicol acetyltransferases chemi- tion (Fig. 10). Gram-negative bacteria prefer b-lactam cally inactivate chloramphenicol in both Gram- ring hydrolysis, whereas resistance to in Gram-posi- positive and Gram-negative bacteria (Schwarz et al. tive bacteria is mostly achieved by modifications of 2004). the target site of antibiotics (Bush 2013; Bush and Bacteria have also developed mechanisms that Fisher 2011). decrease the antibiotic uptake by preventing the Another bacterial strategy to cope with the presence antibiotic from reaching its intracellular or periplas- of antibiotics is to produce enzymes that inactivate the mic target. Hydrophilic molecules such as b-lactam drug by adding specific chemical moieties to this antibiotics, tetracyclines, and some fluoroquinolones compound. In the case of Gram-negative bacteria, the are translocated through the membrane by water-filled aminoglycoside group of antibiotics becomes ineffec- diffusion channels known as porins (i.e., OmpF, tive due to the phosphorylation, adenylation, or OmpC, and PhoE) (Pages et al. 2008). Bacteria acetylation of the antibiotic molecule (Munita and decrease porin-mediated antibiotic uptake by either a 123 258 Phytochem Rev (2019) 18:241–272 Fig. 10 Diagrammatic representation of mechanisms of antibi- and chemical modification of antibiotic molecules (6). More- otic resistance. Antibiotic resistance can be executed in many over, Gram-negative bacteria are resistant to penicillin and other different ways, such as efflux of the antibiotics from the hydrophilic antibiotics due to the low permeability of their outer bacterial cell (1); changing membrane potential, which prevents membrane, as well as low expression of porins (7). Furthermore, antibiotic molecules from entering (2); bypassing target site of bacteria can gain and exchange the resistance genes through the antibiotic through incorporation of changed precursor (3) or transduction (phage-mediated), conjugation (acquiring plasmid changing target site by methylation of RNA, mutations, etc. (4). DNA) and transformation (incorporation of naked DNA) (8) Antibiotic action can also be abolished through degradation (5) shift in the type of porins expressed (Domenech- (PACE) (Hassan et al. 2013). These families differ in Sanchez et al. 2003), or by changing the level of porin terms of structural conformation, a range of substrates, expression, as well as by impairing the function of energy sources, and in the types of bacterial organisms these channels (Fernandez and Hancock 2012). More- in which they are distributed (Soto 2013). over, the described changes in the membrane perme- The last common mechanism of antibiotic resis- ability are often accompanied by an increased tance is interfering with an antibiotic target site either expression of efflux pumps, in both Gram-negative by preventing the antibiotic to reach its binding site and Gram-positive bacteria. The efflux pumps may be (target protection) or by target site modification that substrate-specific (tetracycline or macrolides, such as decreases an antibiotic binding affinity. Examples of erythromycin in pneumococci) or have broad substrate drugs affected by this mechanisms include tetracy- specificity, which is common for multidrug resistance cline [Tet(M) and Tet(O)], fluoroquinolones (Qnr), bacteria (MDR) (Poole 2005). There are six major and fusidic acid (FusB and FusC) resistance (Munita families of efflux pumps: the ATP-binding cassette and Arias 2016). Tet(O) and Tet(M) proteins interact (ABC) superfamily (Lubelski et al. 2007), the major with the ribosome and dislodge the tetracycline from facilitator superfamily (MFS) (Pao et al. 1998), the its binding site in a GTP-dependent manner, restoring multidrug and toxic compound extrusion (MATE) (Lu the protein synthesis (Donhofer et al. 2012; Li et al. 2016), the small multidrug resistance (SMR) family 2013). The quinolone resistance protein Qnr belongs (Bay et al. 2008) (a member of the much larger drug/ to the pentapeptide repeat protein family and it acts as metabolite transporter family (DMT) (Piddock 2006)), a DNA homologue competing for the DNA binding the resistance nodulation division (RND) superfamily site of the DNA gyrase and topoisomerase IV. The (Nikaido and Takatsuka 2009), and newly discovered reduction in the DNA gyrase–DNA interaction pre- proteobacterial antimicrobial compound efflux pump vents the quinolone molecule from forming the lethal 123 Phytochem Rev (2019) 18:241–272 259 DNA–quinolone complex (Aldred et al. 2014). The NorA efflux pump inhibitory activity. Although the antibiotic target site changes may also result from sarothrin alone is a weak antimicrobial agent, it could point mutations in the genes encoding these targets, increase the activity of other antimicrobial compounds enzymatic alterations of the binding sites by methy- by blocking the bacterial efflux pumps (Bame et al. lation, or by ‘‘replacement or bypass of the target site’’. 2013). Furthermore, Fujita et al. (2005) restored the Classical examples of mutational resistance include effectiveness of tetracycline against MRSA, by development of rifampin (RIF) resistance (Campbell baicalein (11)-mediated inhibition of tetracycline et al. 2001) and the resistance to oxazolidinones efflux pump (Tet(K)). However, baicalein inhibited (linezolid and tedizolid) (Chen et al. 2013). The the transport of tetracycline in E. coli KAM32, which resistance to erythromycin is achieved through the lacks the AcrAB pump. This latter observation enzymatic modification of its target site by the suggests that baicalein inhibits some other extrusion ribosome methylation, which is being catalyzed by pump(s) for tetracycline (Fujita et al. 2005). EGCG ribosomal methylases (encoded by the Erm genes) (42) also inhibited Tet(K) pumps in staphylococci, (Leclercq and Courvalin 2002). The ‘‘replacement or presumably by inhibiting the expression of Tet bypass of the target site’’ strategy is used by the proteins (Roccaro et al. 2004). bacteria that are resistant to vancomycin. This antibi- In contrast to Gram-positive bacteria, Gram-nega- otic kills bacteria by preventing their cell wall tive bacteria are resistant to wide range of antibiotics, synthesis by binding to nascent peptidoglycan precur- mainly due to the low permeability of their cell sors (D-Ala-D-Ala) and forming a cap that results in the membrane. The main mechanism attributed to their loss of cross-linking in the polypeptide chain (Gardete resistance consists of MexAB-OprM and AcrAB-TolC and Tomasz 2014). The vancomycin-resistant bacteria efflux pumps as well as low porin expression (Brei- produce a different variant of the peptidoglycan denstein et al. 2011). Daidzein (21), an isoflavone, precursors (D-alanyl-D-serine or D-alanyl-D-lactate) or showed a very slight modulatory effect on M. smeg- completely destroy the ‘‘normal’’ D-Ala-D-Ala ending matis as an efflux pump inhibitor (Lechner et al. precursors (Hiramatsu 2001; McGuinness et al. 2017). 2008b). However, molecular docking calculations and Occasionally the resistance to antimicrobial agents in vitro assays point it as an inhibitor of the MexAB- can be obtained via combined mechanisms. For OprM and AcrAB-TolC tripartite efflux pumps exist- instance, gentamicin resistance, although it does not ing in P. aeruginosa and E. coli (Aparna et al. 2014). rely on the antibiotic modification, it is executed thru Daidzein potentiated the efficacy of carbenicillin and altering the membrane potential and efflux, as well as levofloxacin antibiotics against both E. coli and P. 16S rRNA methylation (Waglechner and Wright aeruginosa. Furthermore, authors suggested that 2017). daidzein possibly circumvents the efflux resistance mechanism. The molecular dynamics studies per- Inhibition of bacterial efflux pumps formed by Suriyanarayanan and Sarojini Santhosh (2015) reported that quercetin (32) could bind to M. Bacterial drug efflux pumps can efflux a large number tuberculosis Mmr and E. coli EmrE efflux pumps, of structurally unrelated drugs and have a significant suggesting that it may downregulate the drug efflux role in the development of antimicrobial resistance in and thus play a role of non-antibiotic adjuvant. A study bacteria (Lubelski et al. 2007). Notably, Wang et al. by Dey et al. (2015) examined the antimicrobial (2014) and Lechner et al. (2008b) showed that activity of EGCG (42) and quercetin against drug- biochanin A (20), along with its metabolite genistein resistant M. tuberculosis and b-lactamase producing (22) are potentiators of the antibacterial activities of K. pneumoniae and demonstrated the antimicrobial ˇ ˇ norfloxacin and berberine in wild-type S. aureus and effects of both flavonoids. The results of Kurincic et al. M. smegmatis, respectively. However, the inhibitory (2012) demonstrated that EGCG shows antibacterial effect of those flavonoids on NorA MDR efflux pump activity and enhances antibiotic effects against clinical (MFS family) was said to be rather moderate. Mild isolates of P. aeruginosa, and EGCG was proposed to inhibitory effects were also reported for the sarothrin act as an inhibitor of the efflux pump MexAB-OprM (18) from Alkanna orientalis, which inhibited the (Kurincˇicˇ et al. 2012). Similarly, EGCG, by impairing growth of M. smegmatis and S. aureus and possessed CmeDEF drug efflux systems, partially reversed the 123 260 Phytochem Rev (2019) 18:241–272 ˇ ˇ drug resistance of Campylobacter spp, (Kurincic et al. with the regulation of the activities of different 2012). Moreover, Christena et al. (2015) showed the proteins and molecular processes, and there is need role of efflux pumps in quorum sensing, cell-to-cell for further studies, especially regarding their syner- signaling, and biofilm formation. gistic action. Altogether, these reports suggest that flavonoids act rather as efflux pumps potentiators than inhibitors, and Combined action of flavonoids and antibiotics the mechanistic relationship between efflux pumps and biofilm formation requires further studies. The As already mentioned above, one of the suggested need for further studies is highlighted by the fact that approaches for improving the antibiotic efficiency efflux pumps make antibiotics ineffective, and the against bacteria involves the use of flavonoids as combination therapy along with the existing flavonoid potentiators (Brynildsen et al. 2013). Moreover, inhibitors could solve this problem. flavonoids are used by cells for their protection against the harmful effects of ROS (Baldim et al. 2017; Antimicrobial action vs ROS production Brunetti et al. 2013; Pietta 2000; Prochazkova et al. 2011). Notably, Brynildsen et al. (2013) proposed to It must be accepted that the mammalian innate increase the antibiotic efficacy not by impairing the immune system has evolved with sophisticated mech- organism’s ROS defense systems by adjuvants, such as flavonoids, but by amplifying the endogenous ROS anisms to recognize and kill bacteria. These processes are mediated mainly by the phagocytosis mechanism, production, which should compromise its ability to by which macrophages and neutrophils engulf bacte- cope with an oxidative attack from the antibiotic. rial cells to kill them by an ‘‘oxidative burst’’ produced Kohanski et al. (2007) demonstrated that quinolones, by the NADPH oxidase, a main source for the b-lactams, and aminoglycosides stimulated hydroxyl generation of ROS in activated neutrophils and radical formation via the Fenton reaction. Addition- macrophages (Nunes et al. 2013). ally, both the iron chelator and the hydroxyl radical A lot of studies have showed that the bactericidal quencher, which could be flavonoids, attenuate killing antibiotics such as b-lactams, aminoglycosides, and by bactericidal drugs, which suggest that hydroxyl fluoroquinolones induced oxidative stress, regardless radicals contribute to bactericidal antibiotic-mediated of their specific targets, and participated in the ROS- cell death. Furthermore, uptake of aminoglycoside antibiotic bacteria killing [reviewed by Dwyer et al. antibiotics (AGs: gentamycin, amikacin, neomycin, (2014) and Vatansever et al. (2013)]. On the other streptomycin, spectinomycin, and tobramycin) is hand, several other reports failed to show the link driven by the proton motive force (Taber et al. between ROS and antibiotic-mediated killing [re- 1987), which is abolished when ROS concentrations viewed by Van Acker and Coenye (2017)]. These are increased over wild-type levels (Ezraty et al. 2013; inconsistent data may have resulted from the presence Farha and Brown 2013). Flavonoids like other iron of ROS, which are generated through the hyperacti- chelators, protect against AGs by blocking AGs vation of normal cell metabolism, as well as the related uptake via the impairment of Fe-S cluster synthesis difficulty or even the impossibility to completely resulting in the impendence of the PMF (Ezraty et al. separate the effects of decreased ROS levels and ROS 2013). production as a consequence of the action of antibi- The most common mechanism of AG resistance is otics (Dwyer et al. 2014; Van Acker and Coenye the chemical modification by bacterial aminogly- 2017). Flavonoids are considered as efficient ROS coside-modifying enzymes (AMEs), acetyltrans- scavengers; however, the flavonoid concentration in ferases (AACs), nucleotidyltranferases (ANTs), or human plasma and most tissues is too low to effec- phosphotransferases (APHs) (Ramirez and Tolmasky tively reduce ROS (Brunetti et al. 2013). Furthermore, 2010). Unfortunately, only few flavonoids were flavonoid ROS scavenger usage should be carefully reported as inhibitor of these enzymes. The quercetin considered, since low ROS concentrations are, on the (32) was proposed as an APH inhibitor (Daigle et al. contrary, beneficial for bacteria and can induce 1999; Shakya et al. 2011) and was shown to occupy the resistance. Thus, the function of flavonoids as an ATP binding site and to interact with the enzyme antimicrobial potentiator should rather be associated APH(2 )-IVa through a series of hydrogen bonds. 123 Phytochem Rev (2019) 18:241–272 261 Moreover, apigenin (10) although did not affect compound (French 2006). However, bactericidal APH(2 )-IVa, it was able to inhibit the closely related studies depend on determining the Colony-Forming enzyme APH(2 )-IIa. Furthermore, metal cations Units (CFU) number, while some flavonoids have 2? 3? 6? 2? 2? 2? 2? 2? (Mg ,Cr ,Cr ,Mn ,Co ,Ni ,Cu ,Zn , been reported to induce the formation of multicellular 2? 3? Cd , and Au ) have been demonstrated to inhibit aggregates. Thus, decrease in CFU numbers may the AG acetyltransferase activity and to increase the result rather from the cell aggregation, than the efficacy of AGs in resistant strains (Li et al. 2015) bactericidal action of a tested compound. Since Therefore, flavonoids as chelators could be used as a MBC studies of flavonoids are often unreliable, other potential inhibitors of AMEs. However, such flavo- assays must be used to ensure the lack of cell noid application requires future research. aggregation. Microscopic study-supported time-kill It should be considered, that combined use of assays suggested by Cushnie et al. (2007) can be a antibiotics with flavonoids can lead to some negative solution to this problem. effects. For example, isoquercetin (33) showed antag- Furthermore, many other factors may affect the onism with aminoglycoside antibiotics such as results of antimicrobial in vitro studies, either it is the neomycin, kanamycin, gentamicin, and amikacin MIC, MBC studies or it is the Kirby-Bauer’s antibiotic when tested with E. coli 27 strain. However, quercetin test. The most important variables include the sensi- did not affect the antibacterial activity of the amino- tivity of strains, antimicrobial potential of a studied glycoside antibiotics. Moreover, both isoquercetin and compound, the type of medium and the optical density quercetin (32) did not affect the action of aminogly- of the inoculum (CLSI 2017). Clinical and Laboratory cosides against a multiresistant strain of S. aureus Standards Institute (CLSI) is one of the organizations (Veras et al. 2011). that standardized many of these variables (CLSI 2017). For example, Mu¨ller-Hinton broth/agar is accepted as a standard growing medium for antimi- Testing antimicrobial activities and reasons crobial susceptibility testing, while the cell density of for discrepancies in results the inoculum for broth microdilution assay is typically at 5 9 10 (Wiegand et al. 2008). However, not all Antimicrobial flavonoids are often described by the research teams follow CLSI guidelines, or even any minimum inhibitory concentration (MIC), which is guidelines at all. Moreover, there are limitations to being their minimum concentration that causes visible each antimicrobial assay, for example, a flavonoid inhibition of bacterial growth. MIC assessment is with poor agar diffusion abilities will yield weak usually the first step of evaluation of new antimicro- results in agar diffusion test, despite its possibly good bials and it is determined in agar dilution or broth antimicrobial activity (Zheng et al. 1996). Further- dilution assays (O’Neill and Chopra 2004). Plant more, the solvent used for the preparation may extracts with MIC B 100 lg/mL and purified com- influence the extract contents and affect the antimi- pounds with MIC B 10 lg/mL are considered crobial activity. Crude methanolic plant extracts promising (Rios and Recio 2005). However, MIC typically have the highest concentration and highest parameter describes the bacteriostatic activity of the number of flavonoids, and thereby the strongest given compound only, same as Kirby-Bauer’s agar antimicrobial activity (Dar et al. 2016). However, diffusion test, which is also commonly used in the sometimes the pure compounds are isolated, which are antimicrobial susceptibility testing (Ahmed et al. usually hydrophobic and may precipitate in wrong 2016; Awouafack et al. 2011; Tohma et al. 2016). solvents, e.g., water (Lof et al. 2011). This will lead to However, with the increasing number of immuno- their reduced contact with the bacterial cells and thus compromised patients, it is important to develop a decreased activity. Notably, some flavonoids have bactericidal drug, rather than just a bacteriostatic been known to form salts in alkaline solvents that can (Corti et al. 2009). Bactericidal activity is determined also influence their biological activities (Cushnie et al. by the minimum bactericidal concentration (MBC) in 2003). Dimethyl sulfoxide (DMSO) that is typically time-kill assays. MBC and MIC parameters comple- used to dissolve isolated flavonoids offers good ment each other and MBC below the four times MIC polyphenol solubility; however, the DMSO may also value suggests the bactericidal action of a tested 123 262 Phytochem Rev (2019) 18:241–272 affect results by interacting with bacterial membranes compounds is typically described by the fractional (Mi et al. 2016). inhibitory concentration index (FICI) (Wang et al. 2014) MICðÞ antibiotic alone The most potent antimicrobial flavonoids FICI ¼ MICðÞ antibiotic combined with compound MICðÞ compound alone In Table 1, we have summarized antimicrobial MICðÞ compound combined with antibiotic flavonoids with the MIC value below 10 lg/mL. We chose the MIC value as a determinant, because it is the Staphylococcus aureus with many resistant strains most commonly used characteristic of novel antimi- is one of the most dangerous pathogens nowadays crobials, including flavonoids. MBC values (if tested) (Lindsay 2013). Thus, there is an understandable are also presented in the Table 1. Given the possibility desire to find agents that would enhance the available of cell aggregation during MBC studies, as well as anti-staphylococcal drugs, and studies of most other potential reasons for results discrepancies, these research teams are focused on the synergy of data must be interpreted with caution. In majority of flavonoids and antibiotics against resistant S. aureus studies cited in Table 1, mechanisms of antibacterial strains. Reports of synergy and additive effects of action of tested flavonoids have not been elucidated. flavonoids and antibiotics are summarized in Table 2. Mechanism of action and structure–activity relation- Although the involvement of flavonoids in the bacte- ship studies are usually conducted by research teams rial growth control is extensively studied, their of different specialty, compared to those who report complexation with antibiotics remains poorly novel antimicrobial agents. It is understandable, since understood. those areas of studies require different approach and expertise. It does, however, create a knowledge gap, where a lot of compounds are known for their Concluding remarks antimicrobial activity, but little detail is known about mechanism of action of every one of them. Some of Recently, CDC estimated that one in five pathogens the compounds present in the Table 1 had been studied from hospital-acquired infections represents mul- for their mechanism of action in different studies and tidrug-resistant strain (MDR) (Weiner et al. 2016), have been described above. while there is no progress in the development of new classes of antibiotics. Hence, there is a serious need for finding new antimicrobial agents or at least substances Examples of synergy and additive effect that would enhance the effectiveness of current drugs between flavonoids and antibiotics (Abreu et al. 2012). Notably, many flavonoids show strong antimicrobial effects and/or synergy with Recently, there has been a growing interest in ‘‘conventional’’ antibiotics. There are also reports of uncovering novel antibiotic adjuvants through sys- flavonoids inhibiting bacterial virulence factors, such tematic approaches. Notably, the ability of plant as hemolysis activity of S. aureus (Qiu et al. 2010). metabolites to enhance the activity of antibiotics has Importantly, most of the flavonoids are considered been widely reported (Sana et al. 2015). These nontoxic because of their ubiquity in all sorts of plant- compounds that have potential activity against patho- derived foods and beverages. Few toxicity studies genic bacteria are variably been termed modulating, support that notion. Dzoyem et al. (2013) conducted resistance modifying, or reversal adjuvants. In this experiments on silkworm larvae, which supported low review, we provide examples of synergy between or no toxicity of tested flavonoids. Single-dose toxicity antibiotics and flavonoids. Most of the researchers studies performed on lab rats also failed to determine propose flavonoids to be resistance modifying agents methanolic extract of flavonoids as toxic (Kuete et al. (RMAs). The mechanisms of RMA action may 2007). Moreover, Ames test showed no mutagenic include inhibition of efflux pumps or antibiotic- effect of the selected flavonoids (Bagla et al. 2014). degrading enzymes and membrane permeabilization Daily intake of flavonoids is estimated at (Abreu et al. 2012). Interaction of two antimicrobial 123 Phytochem Rev (2019) 18:241–272 263 Table 1 Strongest antimicrobial flavonoids reported in recent S. aureus; NT—not tested; PPSA—penicillinase-producing S. years (EGCG—epigallocatechin gallate; MRSA—methicillin- aureus; VISA—vancomycin-intermediate S. aureus; VRE— resistant Staphylococcus aureus; MSSA—methicillin-sensitive vancomycin-resistant Enterococci) Flavonoid MIC/MBC (lg/mL) Strain References Flavone 1.95/3.9 P. vulgaris, P. mirabilis Basile et al. (2010) Isolupalbigenin 1.56–3.13/6.25–25 MRSA Sato et al. (2006) Galangin 0.89–14.16/ MSSA, MRSA, Pepeljnjak and Kosalec (2004) 1.38–23.44 Enterococcus spp., P. aeruginosa Rutin 8/16 K. pneumoniae Djouossi et al. (2015) Rhamnoisorobin 1-2/NT S. aureus, P. aeruginosa, Tatsimo et al. (2012) S. typhi 2-hydroxylupinifolinol 2.3–4.7/NT MSSA, MRSA, Thongnest et al. (2013) S. pyrogenes, B. cereus 3 -O-methyldiplacol 2–4/NT B. cereus, E. faecalis, Smejkal et al. (2008) L. monocytogenes, S. aureus, S. epidermidis 2,8-diprenyleriodictyol 0.5–4/NT MSSA, MRSA Dzoyem et al. (2013) Diplacone 2–16/4.9–39.2 MRSA Navratilova et al. (2016) Hesperetin 4–32/NT S. aureus Lopes et al. (2017) Naringenin C 2.8/NT M. tuberculosis Chen et al. (2010) Pinocembrin 3.5/NT M. tuberculosis Chou et al. (2011) Sepicanin A 2.9/2.9 MRSA Radwan et al. (2009) Dihydrokaempferol 6.25/12.5–25 VRE, S. aureus Tajuddeen et al. (2014) Bartericin A 0.31–0.61/NT C. freundii, S. dysenteriae, Kuete et al. (2007) B. cereus, S. aureus, S. faecalis (among others) Isobavachalcone 0.3–0.6/0.6–1.2 S. faecalis, S. aureus, Mbaveng et al. (2008) E. aerogenes, E. cloacae (among others) Panduratin A 1–2/4–8 E. faecalis, E. faecium Rukayadi et al. (2010) Phloretin 1/NT S. aureus Lopes et al. (2017) Licochalcone A 2-8/NT MSSA, MRSA Qiu et al. (2010) 100–1000 mg/day, depending on the diet (Aherne and effects may be explained by the relatively low O’Brien 2002). In general, no adverse effects have bioavailability and rapid metabolism that leads to been associated with high dietary intakes of flavonoids elimination of most of the flavonoids (Harwood et al. from plant-based food. Flavonoid-rich foods and 2007; Ottaviani et al. 2015). To date, the importance of beverages include tea, red wine, fruit skins, citrus the safe use of flavonoid supplements in pregnancy fruits, berry fruits, and honey (Kumar and Pandey and lactation has not been well established (Hendler 2013). Those foods are typically attributed to many and Rorvik 2009; Mills et al. 2013). Moreover, the use health benefits. The lack of toxicity and natural of green tea extracts was directly associated with occurrence makes flavonoids possibly good food abnormally high levels of liver enzymes (Dostal et al. preservatives. They can be a viable candidate for 2015; Sarma et al. 2008). Obviously, further toxicity replacing synthetic preservatives that are disliked by studies are needed before releasing any food or the consumers (Wu et al. 2013). The lack of adverse medicine containing high amounts of flavonoids. 123 264 Phytochem Rev (2019) 18:241–272 Table 2 Examples of synergy and additives effect between antibiotics and flavonoids (FICI—fractional inhibitory concentration index; EGCG—epigallocatechin gallate; MSSA—methicillin-sensitive Staphylococcus aureus; MRSA—methicillin-resistant S. aureus; PPSA—penicillinase-producing S. aureus, VISA—vancomycin-intermediate S. aureus) Flavonoid Antibiotic FICI Strain References Flavone Vancomycin 0.096 VISA ATCC 700699 Bakar et al. (2012) Oxacillin 0.126 Apigenin Ampicillin, 0.18–0.47 MRSA strains Akilandeswari and Ruckmani Ceftriaxone (2016) Baicalein Tetracycline 0.06–0.12 MRSA strains Fujita et al. (2005) Baicalein Penicillin 0.14–0.25 PPSA strains Qian et al. (2015) Amoxicillin 0.14–0.38 Baicalein Cloxacillin \ 0.02 S. aureus DMST 20651 Eumkeb et al. (2010) Diosmetin Streptomycin 0.39 S. aureus 1199B, RN4220 Wang et al. (2014) Ciprofloxacin 0.09 S. aureus EMRSA-15 Luteolin Ampicillin, 0.82–0.9 MRSA ATCC 43300 Usman Amin et al. (2016) Cephradine, Ceftriaxone, Imipenem, Methicillin Luteolin Ceftazidime 0.37 S. pyogenes DMST Siriwong et al. (2015) Genistein 0.27 30653 - 30655 Genistein Norfloxacin 0.38 S. aureus 1199B, Wang et al. (2014) RN4220, Ciprofloxacin 0.09 S. aureus EMRSA-15 Galangin Cloxacillin \ 0.02 S. aureus DMST 20651 Eumkeb et al. (2010) Morin Ampicillin 0.31 MRSA ATCC 3359 Mun et al. (2015) 0.75 MRSA DPS-1 Myricetin Isoniazid 0.2 M. smegmatis mc 155 Lechner et al. (2008a) Galangin Amoxicillin \ 0.09 E. coli (AREC) Eumkeb et al. (2012) Kaempferide Kaempferide-3-O- glucoside Quercetin Cloxacillin \ 0.02 S. aureus DMST 20651 Eumkeb et al. (2010) Quercetin Ceftriaxone, 0.66–0.84 MRSA ATCC 43300, Usman Amin et al. (2016) Quercetin ? luteolin Imipenem, 0.45–0.65 MRSA Clinical Isolates Rutin ? morin Methicillin 0.8–0.9 EGCG Tetracycline 0.375 MRSA6975, MRSA3202 Navratilova et al. (2016) Oxacillin 0.5 Synthetic Vancomycin 0.97 E. faecium Budzynska et al. (2011) 3-arylideneflavanones Oxacillin 0.01–0.58 S. aureus A3 ‘Synergy’ was defined where the FICI was less than or equal to 0.5; whilst ‘additive’ effects were observed when the FICI was greater than 0.5 and less than or equal to 1.0; greater than 1 and less than 2 as indifferent; Antagonistic effects were observed when the FICI was greater than 2.0 Furthermore, to increase the specificity and safety of Considering the hydrophobic nature of flavonoids, flavonoids more focus on their mechanisms of action few questions are raised regarding their in vivo and a structure–activity relationship is required. activity, like ‘‘how to achieve and sustain their high 123 Phytochem Rev (2019) 18:241–272 265 inhibitors for multidrug efflux pumps of Escherichia coli blood serum concentration?’’ Their structural modifi- and Pseudomonas aeruginosa using in silico high- cations or use of drug carriers may be essential to throughput virtual screening and in vitro validation. PLoS modulate their infiltration into the bloodstream. On the ONE 9:e101840 other hand, getting to know flavonoid metabolism in Appelbaum PC (2012) 2012 and beyond: potential for the start of a second pre-antibiotic era? J Antimicrob Chemother mammalian cells may be helpful in preventing their 67:2062–2068 rapid catabolism. Thus, determining if flavonoids are Arora A, Byrem TM, Nair MG, Strasburg GM (2000) Modu- effective antimicrobials at in vivo environment lation of liposomal membrane fluidity by flavonoids and remains crucial. Finally, flavonoids maintain their isoflavonoids. Arch Biochem Biophys 373:102–109 Awolola GV, Koorbanally NA, Chenia H, Shode FO, Baijnath H biological activity, thanks to a finely regulated trans- (2014) Antibacterial and anti-biofilm activity of flavonoids port and accumulation system that allow entrance into and triterpenes isolated from the extracts of Ficus Sansi- different subcellular compartments. Nevertheless, a barica warb. Subsp. Sansibarica (Moraceae) extracts. Afr J comprehensive view of the phenomenon has not yet Tradit Complement Altern Med 11:124–131 Awouafack MD, Spiteller P, Lamshoft M, Kusari S, Ivanova B, been proposed and is still under investigation. Tane P, Spiteller M (2011) Antimicrobial isopropenyl-di- hydrofuranoisoflavones from Crotalaria lachnophora. Compliance with ethical standards J Nat Prod 74:272–278 Bagla VP, McGaw LJ, Elgorashi EE, Eloff JN (2014) Antimi- Conflict of interest The authors have declared that there is no crobial activity, toxicity and selectivity index of two conflict of interest. biflavonoids and a flavone isolated from Podocarpus henkelii (Podocarpaceae) leaves. BMC Complement Open Access This article is distributed under the terms of the Altern Med 14:383 Creative Commons Attribution 4.0 International License (http:// Bakar NS, Zin NM, Basri DF (2012) Synergy of flavone with creativecommons.org/licenses/by/4.0/), which permits unrest- vancomycin and oxacillin against vancomycin-intermedi- ricted use, distribution, and reproduction in any medium, pro- ate Staphyloccus aureus. Pak J Pharm Sci 25:633–638 vided you give appropriate credit to the original author(s) and Baldim JL, de Alcantara BGV, Domingos ODS, Soares MG, the source, provide a link to the Creative Commons license, and Caldas IS, Novaes RD, Oliveira TB, Lago JHG, Chagas- indicate if changes were made. Paula DA (2017) The correlation between chemical structures and antioxidant, prooxidant, and antitrypanoso- matid properties of flavonoids. 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Comprehensive review of antimicrobial activities of plant flavonoids

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