Interactions with Microbial Proteins Driving the Antibacterial Activity of Flavonoids

Abstract

Flavonoids are among the most abundant natural bioactive compounds produced by plants. Many different activities have been reported for these secondary metabolites against numerous cells and systems. One of the most interesting is certainly the antimicrobial, which is stimulated through various molecular mechanisms. In fact, flavonoids are effective both in directly damaging the envelope of Gram-negative and Gram-positive bacteria but also by acting toward specific molecular targets essential for the survival of these microorganisms. The purpose of this paper is to present an overview of the most interesting results obtained in the research focused on the study of the interactions between flavonoids and bacterial proteins. Despite the great structural heterogeneity of these plant metabolites, it is interesting to observe that many flavonoids affect the same cellular pathways. Furthermore, it is evident that some of these compounds interact with more than one target, producing multiple effects. Taken together, the reported data demonstrate the great potential of flavonoids in developing innovative systems, which can help address the increasingly serious problem of antibiotic resistance.

Keywords: ATP synthetase; DNA gyrase; antibacterial activity; antibiofilm activity; bioactive natural compounds; efflux pumps; enzyme inhibitor; flavonoids.

Figure 1

Basic structures of the main flavonoid classes.

Figure 2

Main action mechanisms of flavonoids antibacterial activity. Flavonoids preferred substituents identified for each activity are also shown.

Figure 3

Molecular docking analysis of cPAC in the AcrAB–TolC efflux pump. (A) Complete side view with ribbon representation of docked complexes of efflux pump proteins with A-type cPAC molecule. The inset views show the electron density map (2F0–Fc) of cPAC in binding sites of multidrug efflux pump exit duct (TolC in pink), adapter (AcrA in gold), and transporter (AcrB in blue) proteins. OM, outer membrane; PP, periplasmic space; IM, inner membrane. Adapted from [40], Adv. Sci. 2019.

Figure 4

Molecular modeling of binding mechanisms of cholesterol (CHO) to listeriolysin O (LLO) and the effects of fisetin (FSN) on such binding. (A) LLO is organized into four domains (D1-D4). (B) I–III, Comparison of the distances (in nm) between the Cα atoms of Gly490 and Gly400 is shown in the structures of free LLO (I), the LLO–CHO complex (II), and the LLO–FSN complex (III). The average distance of the LLO–CHO complex is 2.35 nm. In the absence of ligand, the average distance between the defined points is 2.41 nm, and in the LLO–FSN complex, the distance is 2.79 nm. Adapted from [99], J. Infect. Dis. 2015.