Plant Metabolites as Potential Agents That Potentiate or Block Resistance Mechanisms Involving β-Lactamases and Efflux Pumps

Abstract

The dramatic increase in antimicrobial resistance (AMR) in recent decades has created an urgent need to develop new antimicrobial agents and compounds that can modify and/or block bacterial resistance mechanisms. An understanding of these resistance mechanisms and how to overcome them would substantially assist in the development of new antibiotic chemotherapies. Bacteria may develop AMR through multiple differing mechanisms, including modification of the antibiotic target site, limitation of antibiotic uptake, active efflux of the antibiotic, and via direct modification and inactivation of the antibiotic. Of these, efflux pumps and the production of β-lactamases are the most common resistance mechanisms that render antibiotics inactive. The development of resistance-modifying agents (particularly those targeting efflux pumps and β-lactamase enzymes) is an important consideration to counteract the spread of AMR. This strategy may repurpose existing antibiotics by blocking bacterial resistance mechanisms, thereby increasing the efficacy of the antibiotic compounds. This review focuses on known phytochemicals that possess efflux pump inhibitory and/or β-lactamase inhibitory activities. The interaction of phytochemicals possessing efflux pumps and/or β-lactamase inhibitory activities in combination with clinical antibiotics is also discussed. Additionally, the challenges associated with further development of these phytochemicals as potentiating agents is discussed to highlight their therapeutic potential, and to guide future research.

Keywords: antibiotic potentiation; antibiotic resistance; combinational therapies; efflux pump inhibitor; phytochemicals; β-lactamase inhibitor.

Figure 1

Base structures of (a) phenolic acid, (b) coumarins, (c) flavonoids, (d) lignans, (e) stilbenes, (f) tannins and (g) terpenoids.

Figure 2

Efflux pump families.

Figure 3

Inactivation of penicillin by beta lactamase enzymes. The red line indicates the peptide bond that is hydrolysed by the enzyme.

Figure 4

(a) Berberine, (b) 1, 4-naphthalenedione, (c) 2-methoxy chrysophanol (d) aranorosin, (e) baicalein, (f) capsaicin, (g) catharanthine, (h) conessine, (i) epigallocatechin gallate, (j) ferruginol, (k) indirubin, (l) kaempferol rhamnoside, (m) oleanolic acid, (n) osthol, (o) reserpine and (p) silybin.

Figure 5

Efflux pump inhibitory mechanisms (indicated by the red crosses), including proton motive force disruption, blockage of ATP synthesis, altering the integrity of the membrane permeability, down-regulating gene expression and targeting the functional assembly of the efflux pump. The black rectangles indicate altered membrane permeability.

Figure 6

β-lactamase inhibitor mechanism of action.