See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/328423406 Antibacterial activity of flavonoids and their structure–activity relationship: An update review Article in Phytotherapy Research · October 2018 DOI: 10.1002/ptr.6208 CITATIONS READS 24 1,003 4 authors: Faegheh Farhadi Bahman Khameneh Mashhad University of Medical Sciences Mashhad University of Medical Sciences 5 PUBLICATIONS 25 CITATIONS 35 PUBLICATIONS 444 CITATIONS SEE PROFILE SEE PROFILE Mehrdad Iranshahi Milad Iranshahi Mashhad University of Medical Sciences Mashhad University of Medical Sciences 234 PUBLICATIONS 5,009 CITATIONS 35 PUBLICATIONS 582 CITATIONS SEE PROFILE SEE PROFILE Some of the authors of this publication are also working on these related projects: Study the effect of natural products on autoimmune diseases View project Antibacterial Activity of Silver Nanoparticle- Loaded Soft Contact Lens Materials: The Effect of Monomer Composition . View project All content following this page was uploaded by Faegheh Farhadi on 29 October 2018. The user has requested enhancement of the downloaded file. Received: 18 January 2018 Revised: 5 August 2018 Accepted: 12 September 2018 DOI: 10.1002/ptr.6208 REVIEW Antibacterial activity of flavonoids and their structure–activity relationship: An update review Faegheh Farhadi1 | Bahman Khameneh2 | Mehrdad Iranshahi3 | Milad Iranshahy1,3 1 Department of Pharmacognosy, School of Pharmacy, Mashhad University of Medical Based on World Health Organization reports, resistance of bacteria to well‐known Sciences, Mashhad, Iran antibiotics is a major global health challenge now and in the future. Different strate- 2 Department of Pharmaceutical Control, School of Pharmacy, Mashhad University of gies have been proposed to tackle this problem including inhibition of multidrug resis- Medical Sciences, Mashhad, Iran tance pumps and biofilm formation in bacteria and development of new antibiotics 3 Biotechnology Research Center, with novel mechanism of action. Flavonoids are a large class of natural compounds, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, have been extensively studied for their antibacterial activity, and more than 150 arti- Mashhad, Iran cles have been published on this topic since 2005. Over the past decade, some prom- Correspondence ising results were obtained with the antibacterial activity of flavonoids. In some cases, Milad Iranshahy, Pharm. D., PhD, Department of Pharmacognosy, School of Pharmacy, flavonoids (especially chalcones) showed up to sixfold stronger antibacterial activities Mashhad University of Medical Sciences, than standard drugs in the market. Some synthetic derivatives of flavonoids also Mashhad, Iran. Email: [email protected] exhibited remarkable antibacterial activities with 20‐ to 80‐fold more potent activity Funding information than the standard drug against multidrug‐resistant Gram‐negative and Gram‐positive Mashhad University of Medical Sciences bacteria (including Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus). This review summarizes the ever changing information on antibacterial activ- ity of flavonoids since 2005, with a special focus on the structure–activity relationship and mechanisms of actions of this broad class of natural compounds. KEYWORDS antibacterial, biofilm, chalcones, flavonoids, multidrug resistance, natural compounds 1 | INTRODUCTION therapy via natural antibacterial substances and also using drug deliv- ery systems are important approaches in this field. Over the past Antibacterial resistance is the major global health challenge and decade, many classes of natural products intensively studied for this threats the public health. (Seleem, Pardi, & Murata, 2017). The anti- purpose, especially against multidrug‐resistant Gram‐negative and bacterial resistance mechanisms can be divided into two categories: Gram‐positive bacteria (Barbieri et al., 2017; Hassanzadeh, (a) innate or intrinsic resistance and (b) acquired resistance. Intrinsic Rahimizadeh, Bazzaz, Emami, & Assili, 2001; Iranshahi, Fata, Emami, resistance is mainly a feature of a particular bacterium and is based Jalalzadeh Shahri, & Bazzaz, 2008; Iranshahi, Hassanzadeh‐Khayat, on biological properties of bacteria. The second mechanism of resis- Bazzaz, Sabeti, & Enayati, 2008; Salar Bashi, Bazzaz, Sahebkar, tance is mainly due to the acquisition of resistance genes by other Karimkhani, & Ahmadi, 2012). The results of these efforts were devel- pathogenic bacteria or chromosomal mutation and combination of opment of new antibacterial agents, such as quinine (quinolones and these two mechanisms. Regulatory genes controlling multidrug resis- bedaquiline) and coumarin derivatives (novobiocin; Venugopala, tance by expression of efflux pump and bacterial biofilm formation Rashmi, & Odhav, 2013). also show important roles in antibacterial resistance (Frieri, Kumar, & Flavonoids are a large and structurally diverse group of natural Boutin, 2016). Various strategies have been pursued to combat micro- products obtained from nature, and some of them as ingredients of bial resistance. Employing new generations of antibiotics, combination propolis and honey were used in some traditional systems of medicine for the treatment of infectious diseases. The basic structure of flavo- Abbreviations: (FAB), fatty acid biosynthesis; (MOAs), mechanisms of action noid compounds is diphenylpropane (C6–C3–C6) skeleton. The Phytotherapy Research. 2018;1–28. wileyonlinelibrary.com/journal/ptr © 2018 John Wiley & Sons, Ltd. 1 2 FARHADI ET AL. various structure types of flavonoids differ in the degree of oxidation (Kuete et al., 2007; Mbaveng et al., 2008) and licoflavone C (19; from of the C ring and in the substituents patterns in the A and/or B rings, Retama raetam flowers) was active against Escherichia coli via forma- and these differences lead to the diversity of these compounds tion of complexes with extracellular and soluble proteins (MIC (Kumar & Pandey, 2013). Some of the flavonoids (i.e., quercetin) with 7.81 μg/ml; Edziri et al., 2012). a strong background of use in clinical trials are good candidates for Another proposed mechanism is inhibition of bacterial enzymes further clinical studies as antibiotics alone or in combination with (such as tyrosyl‐tRNA synthetase) that was mediated by artocarpin conventional antibiotics (Amin, Khurram, Khattak, & Khan, 2015). (23) extracted from leaves of Artocarpus anisophyllus against B. cereus, In 2005, Cushnie et al. reviewed antibacterial properties of flavo- E. coli, and Pseudomonas putida (Jamil, 2014). Baicalein is an effective noids. However, a large amount of information has been published since bactericide and when combined with cefotaxime, the synergistic then. In the present review, the antibacterial properties of flavonoid effects were observed (Cai et al., 2016). The possible mode of action compounds, which were studied in the last 12 years, have been of baicalein has been studied extensively. It was shown that this com- reviewed. The aim of the present review is the investigation of antibac- pound is able to reduce the Pseudomonas aeruginosa‐induced secretion terial properties of natural, semisynthetic, and synthetic flavonoids, of the inflammatory cytokines IL‐1β,IL‐6, IL‐8, and TNFα, which are their structure–activity relationships and mechanisms of action (MOAs). important for inflammatory injury after P. aeruginosa infection (Luo All relevant databases were searched for the terms “flavonoids” et al., 2016). The results of Chen study indicated that baicalein at con- and “antibacterial,” without limitation from 2005 till December 30, centrations of 32 and 64 μg/ml was able to downregulate the quo- 2017. Information was collected via electronic search using Scopus, rum‐sensing system regulators agrA, RNAIII, and sarA, and gene Pubmed, Web of Science, and Science Direct. expression of intercellular adhesin (ica) in Staphylococcus aureus bio- film producer cells (Chen et al., 2016). Other reports include gancaonin G (27) and semilicoisoflavone B | 2 FLAVONOIDS (28) from Glycyrrhiza uralensis toward vancomycin‐resistant Entero- coccus bacteria with the MIC values of 32 and 64 μg/ml (Orabi, Flavonoids are a group of low‐molecular‐weight polyphenolic sub- Aoyama, Kuroda, & Hatano, 2014). Neocyclomorusin (33) and stances. Chemically, the core structure of flavonoids is based upon a neobavaisoflavone (34) among 19 natural products belonging to terpe- C6–C3–C6 skeleton in which the three‐carbon bridge is usually noids, alkaloids, thiophenes, and phenolics from the methanolic cyclized with oxygen. These compounds are considered as chemotax- extract of Cameroon plants were active against Gram‐negative onomic markers according to the biosynthesis pathway (combination bacteria (Klebsiella pneumonia and Enterobacter cloacae) with the MIC of phenylalanine with three malonyl‐CoA units to form a C‐15 value of 4–8 μg/ml (Mbaveng et al., 2015). Other biological activities chalcone), and they provide attractive color pigments such as yellow, of flavones are summarized in Table 1. red, blue, and purple in plants. The chemical nature of flavonoids Inhibition of the bacterial efflux pump and increase in the suscep- depends on the degree of unsaturation and oxidation of the three‐car- tibility of existing antibiotics (by inducing depolarization of the cell bon chain. Several subgroups of flavonoids have been found in higher membrane) is another possible MOA, and artonin I (24)