Bacterial Efflux Pumps and Their Inhibitors

Abstract

Bacterial multidrug efflux transporters have distinct molecular features and mechanisms that enable their impressive substrate polyspecificity. These transporters are involved in all physiological processes where nonspecific but active transport across membranes is critical for survival and proliferation. Importantly, efflux pumps contribute to bacterial virulence and pathogenesis, as well as the spread of antibiotic resistance in clinics. Transporters belonging to several protein superfamilies have been selected for polyspecificity by evolution and augmented with accessory proteins that extend and couple transport reactions across the inner and outer membranes of the bacterium. As a result, bacteria are equipped with diverse efflux machines that protect cells from a broad variety of toxic compounds including antibiotics and other small molecule therapeutics. The inhibition of such polyspecific biomolecular machines is a challenging task, which still awaits an efficient solution. Here, we review the molecular mechanisms of efflux pumps from Gram‐negative bacteria and recent advances and challenges associated with the discovery of effective inhibitors of these pumps.

Inhibitor of Chromosome Segregation in Pseudomonas aeruginosa from Fungal Extracts

“…Therefore, potential applications of the compound in Gram-negative bacteria necessitate a reduction in the drug efflux. Several strategies have recently emerged to achieve this, including the design of inhibitors of efflux transporters, 57,58 construction of highly permeable bioconjugates, 59 or the use of Gram-negative rules and maps of permeation to construct efflux evaders. 60,61 ■ METHODS Strains and Plasmids.…”

Total Synthesis of Dragmacidins G and H

“…In Gram-negative bacteria, the efflux pumps, like TolC-AcrAB, may inhibit antibacterial activity by excreting compounds. 15 Therefore, we examined the antibacterial activity of a strain in which the gene encoding AcrB was deleted in χ3306 (ΔAcrB). Dragmacidin H showed increased susceptibility with an MIC value of 3.13 μM.…”

Analysis of Orthogonal Efflux and Permeation Properties of Compounds Leads to the Discovery of New Efflux Pump Inhibitors

“…23,24 Investigations of efflux pumps and their substrate profiles and regulatory mechanisms have led to the discovery of efflux pump inhibitors (EPIs) that could potentially become alternative and effective antimicrobial adjuvants. 25,26 However, the discovery and development of such inhibitors is strongly impeded by both the polyspecificity of RND pumps and their synergy with the OM. Compounds that can avoid efflux pumps cannot simultaneously act as inhibitors and possess properties that are distinct from substrates and inhibitors of efflux pumps.…”