Lipid-mediated antimicrobial resistance: a phantom menace or a new hope?

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.

Bacterial susceptibility and resistance to modelin-5

“…53,54 Interestingly, recent studies have suggested that the greater accessibility of phosphate moieties in PE head-groups compared to that in phosphatidylcholine (PC) head-groups may play a role in the selective binding of AMPs to bacterial membranes. 53 PC is the major zwitterionic lipid in eukaryotic membranes 55,95 and M5-NH 2 shows negligible interaction with these membranes 28,32 but strong interaction with bacterial membranes that is comparable to that found here for the P. aeruginosa CM (Table 2). [31][32][33] The next two steps in the interaction of M5-NH 2 with the P. aeruginosa CM were the closely coupled events of a-helix formation and insertion (Fig.…”

High proportions of single-nucleotide variations associated with multidrug resistance in swine gut microbial populations

“…We identified six of seven distinct efflux superfamilies, but we did not identify any proteobacterial antimicrobial compound efflux (PACE) annotations 130 . Although PACE has been demonstrated as prevalent in gram negative bacteria, previous literature has lacked identification in gram negative Bacteroidota , while PACE has been identified in gram positive Firmicutes 131 .…”

Phenotypic convergence of bacterial adaption to sub-lethal antibiotic treatment

“…In particular, the bacterial cell membrane is essential in bacteria and serves as a significant barrier to preventing harmful chemicals from entering the cell ( Willdigg and Helmann, 2021 ). Bacteria induce a cell envelope stress response to resist antibiotics, which are regulatory pathways that detects threats and cause protective reactions, including modifications of the lipopolysaccharides, lipoteichoic acids, peptidoglycan ( Macdermott-Opeskin et al., 2022 ). Changes in membrane composition has been previously reported as one of the most important adaptive mechanisms in bacteria when exposed to toxic compounds such as antibiotics ( Ma et al., 2021 ).…”