Abstract
The proposition of a post-antimicrobial era is all the more realistic with the continued rise of antimicrobial resistance. The development of new antimicrobials is failing to counter the ever-increasing rates of bacterial antimicrobial resistance. This necessitates novel antimicrobials and drug targets. The bacterial cell membrane is an essential and highly conserved cellular component in bacteria and acts as the primary barrier for entry of antimicrobials into the cell. Although previously under-exploited as an antimicrobial target, the bacterial cell membrane is attractive for the development of novel antimicrobials due to its importance in pathogen viability. Bacterial cell membranes are diverse assemblies of macromolecules built around a central lipid bilayer core. This lipid bilayer governs the overall membrane biophysical properties and function of its membrane-embedded proteins. This mini-review will outline the mechanisms by which the bacterial membrane causes and controls resistance, with a focus on alterations in the membrane lipid composition, chemical modification of constituent lipids, and the efflux of antimicrobials by membrane-embedded efflux systems. Thorough insight into the interplay between membrane-active antimicrobials and lipid-mediated resistance is needed to enable the rational development of new antimicrobials. In particular, the union of computational approaches and experimental techniques for the development of innovative and efficacious membrane-active antimicrobials is explored.
Highlights
Antimicrobial resistance (AMR) is one of the foremost threats facing global public health
A 2016 review on antimicrobial resistance gave a conservative estimate of 700,000 deaths caused by AMR annually (O’Neil Jim 2016)
Membrane efflux pumps—the bacterial empire strikes back. Another pertinent mechanism of membrane-mediated AMR is the active efflux of compounds from the bacterial cell membrane by membrane-embedded transport proteins that act as drug efflux pumps (Fig. 1G) (Henderson et al 2021)
Summary
Antimicrobial resistance (AMR) is one of the foremost threats facing global public health. In experimental studies of model lipid bilayers, increases in glycolipid content results in the formation of ordered domains with high structural integrity (Levental et al 2020) which may play a role in modulating antimicrobial mediated membrane disruption.
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