Current Advances in Developing Inhibitors of Bacterial Multidrug Efflux Pumps

Abstract

Antimicrobial resistance represents a significant challenge to future healthcare provision. An acronym ESKAPEE has been derived from the names of the organisms recognised as the major threats although there are a number of other organisms, notably Neisseria gonorrhoeae, that have become equally challenging to treat in the clinic. These pathogens are characterised by the ability to rapidly develop and/or acquire resistance mechanisms in response to exposure to different antimicrobial agents. A key part of the armoury of these pathogens is a series of efflux pumps, which effectively exclude or reduce the intracellular concentration of a large number of antibiotics, making the pathogens significantly more resistant. These efflux pumps are the topic of considerable interest, both from the perspective of basic understanding of efflux pump function, and its role in drug resistance but also as targets for the development of novel adjunct therapies. The necessity to overcome antimicrobial resistance has encouraged investigations into the characterisation of resistance-modifying efflux pump inhibitors to block the mechanisms of drug extrusion, thereby restoring antibacterial susceptibility and returning existing antibiotics into the clinic. A greater understanding of drug recognition and transport by multidrug efflux pumps is needed to develop clinically useful inhibitors, given the breadth of molecules that can be effluxed by these systems. This review discusses different bacterial EPIs originating from both natural source and chemical synthesis and examines the challenges to designing successful EPIs that can be useful against multidrug resistant bacteria.

Fig. (1)

The antibiotic discovery timeline. The 2013 World Economic Forum, adapted from L. L. Silver, Clinical Microbiology Reviews, 2011 [28].

Fig. (2)

A schematic representation of the five common classes of MDR efflux pump. Their general position within the membrane, common substrates and examples of individual and multiple protein components that make up their structures are illustrated.

Fig. (3)

An illustration of the competitive pathways of drug uptake and efflux traversing the lipopolysaccharide bilayer and the outer and inner cell membranes of Gram-negative pathogens. The active extrusion of drug molecules occurs via single and multi-component efflux pumps, where the multi-component tripartite complex comprises a membrane fusion protein, an efflux protein pump in the inner membrane and an outer membrane protein.

Fig. (4)

Chemical structures of EPIs 1 – 3.

Fig. (5)

Chemical structures of EPIs 4 and 5.

Fig. (6)

Chemical structures of EPIs 6 – 12.

Fig. (7)

Chemical structures of EPIs 13 and 14.

Fig. (8)

Chemical structures of EPIs 15-17.

Fig. (9)

Chemical structures of EPIs 18 and 19.

Fig. (10)

Chemical structures of EPIs 20 and 21.

Fig. (11)

Chemical structures of EPIs 22-25.

Fig. (12)

Chemical structures of EPIs 26-28.

Fig. (13)

Chemical structures of EPIs 29-31

Fig. (14)

Chemical structures of EPIs 32-35.

Fig. (15)

Chemical structures of EPIs 36-39.

Fig. (16)

Chemical structures of EPI 40.

Fig. (17)

Chemical structures of EPIs 41-43.

Fig. (18)

Chemical structures of EPIs 44.