Recent advances in understanding the antibacterial properties of flavonoids

Abstract

Antibiotic resistance is a major global problem and there is a pressing need to develop new therapeutic agents. Flavonoids are a family of plant-derived compounds with potentially exploitable activities, including direct antibacterial activity, synergism with antibiotics, and suppression of bacterial virulence. In this review, recent advances towards understanding these properties are described. Information is presented on the ten most potently antibacterial flavonoids as well as the five most synergistic flavonoid–antibiotic combinations tested in the last 6 years (identified from PubMed and ScienceDirect). Top of these respective lists are panduratin A, with minimum inhibitory concentrations (MICs) of 0.06–2.0 μg/mL against Staphylococcus aureus, and epicatechin gallate, which reduces oxacillin MICs as much as 512-fold. Research seeking to improve such activity and understand structure–activity relationships is discussed. Proposed mechanisms of action are also discussed. In addition to direct and synergistic activities, flavonoids inhibit a number of bacterial virulence factors, including quorum-sensing signal receptors, enzymes and toxins. Evidence of these molecular effects at the cellular level include in vitro inhibition of biofilm formation, inhibition of bacterial attachment to host ligands, and neutralisation of toxicity towards cultured human cells. In vivo evidence of disruption of bacterial pathogenesis includes demonstrated efficacy against Helicobacter pylori infection and S. aureus α-toxin intoxication.

Introduction

With antibiotic resistance reaching crisis point in many hospitals around the world [1] and resistance increasing in community-acquired infections as well [2], there is an urgent need to replenish our arsenal of anti-infective agents. Ideally, this should be in the form of new classes of antibacterial agent [3] as the structural alteration of drugs to which resistance has already developed rarely provides a major solution [4]. Inhibition of resistance mechanisms through the development of novel adjuncts also represents an important strategy. The β-lactamase inhibitor clavulanic acid, launched in 1981, remains effective today despite many years of extensive use [5], [6]. A third promising but unproven approach is the development of drugs that target bacterial virulence factors. Rather than inhibiting cellular components necessary for growth or viability, these compounds would ameliorate infection by interfering with aspects of bacterial pathogenesis, e.g. attachment to host tissue [7].

Natural products are a major source of chemical diversity and have provided important therapeutic agents for many bacterial diseases [8]. Most of these agents have been of microbial origin, but the antibacterial properties of plant-derived compounds are attracting increasing attention [9], [10]. This is in part attributed to the fact that plants can be rationally selected for antibacterial testing based on ethnomedicinal use [11]. Flavonoids are a group of heterocyclic organic compounds present in plants and related products, e.g. propolis and honey [12]. Poultices, infusions, balms and spices containing flavonoids as active constituents have been used in many cultures for centuries. Traditional uses include treatment and prevention of various infectious and toxin-mediated diseases, e.g. sores, wound infections [13], acne, respiratory infections [14], gastrointestinal disease [15] and urinary tract infections [16]. Not surprisingly, this family of compounds is the subject of much antibacterial research.

There are 14 classes of flavonoids in total, differentiated on the basis of the chemical nature and position of substituents on the A, B and C rings [17]. The skeleton structures of six of these classes are shown in Fig. 1, with rings named and positions numbered. Most of the reports of flavonoids possessing antibacterial properties can be attributed to these six structures or their isoflavonoid counterparts (flavonoids where ring B is joined at position 3 of ring C instead of position 2). Potential applications for these compounds include modern agents [18] and adjuncts [19] for the treatment of bacterial infections, drugs for treating toxin-mediated disease [20], antivirulence therapies [21] and capture molecules for removing endotoxin from pharmaceutical preparations [22].

In this paper, reports on the diverse range of antibacterial properties exhibited by flavonoids are reviewed. Emphasis is on important developments in the last 6 years, as earlier research has already been discussed [13], [23]. The activity of naturally occurring flavonoids is covered as well as that of semisynthetic and synthetic flavonoids. Proposed structure–activity relationships (SARs) and mechanisms of action (MOAs) are also reviewed. The structures of all the flavonoids discussed are presented in Supplementary Table 1. Readers interested in the more specific topic of antibacterial tea flavonoids or the broader topic of medicinal flavonoids are directed to reviews by Friedman [24] and Cazarolli et al. [25].