Polymyxin and lipopeptide antibiotics: membrane-targeting drugs of last resort

Abstract

The polymyxin and lipopeptide classes of antibiotics are membrane-targeting drugs of last resort used to treat infections caused by multi-drug-resistant pathogens. Despite similar structures, these two antibiotic classes have distinct modes of action and clinical uses. The polymyxins target lipopolysaccharide in the membranes of most Gram-negative species and are often used to treat infections caused by carbapenem-resistant species such as Escherichia coli , Acinetobacter baumannii and Pseudomonas aeruginosa . By contrast, the lipopeptide daptomycin requires membrane phosphatidylglycerol for activity and is only used to treat infections caused by drug-resistant Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. However, despite having distinct targets, both antibiotic classes cause membrane disruption, are potently bactericidal in vitro and share similarities in resistance mechanisms. Furthermore, there are concerns about the efficacy of these antibiotics, and there is increasing interest in using both polymyxins and daptomycin in combination therapies to improve patient outcomes. In this review article, we will explore what is known about these distinct but structurally similar classes of antibiotics, discuss recent advances in the field and highlight remaining gaps in our knowledge.

Microbial Musings – Spring 2022

“…However, with high levels of resistance to other better antibiotics, they are now being used increasingly in clinical practise, and studies on their mechanism of action, mechanisms of resistance and improved clinical applications are undergoing a forced renaissance. Here the authors provide an excellent compilation of the latest research outlining the mechanisms of both action and resistance for these antibiotic types, which also highlights gaps in our current knowledge [12]. For polymyxin resistance the modification of the lipopolysaccharide (LPS) is a recurring theme, through addition of cationic phosphoethanolamine (PEtN) and/or 4-amino-4-deoxy- l -arabinose ( l -Ara4N), catalyzed by enzymes encoded by either intrinsic or acquired genes.…”

“…The first article published in the collection was from new Microbiology Editor Andrew Edwards (@bugsinblood) and colleagues from Imperial College London, UK, which relates to their breakthrough papers, one of which was published in the journal, on the mechanism of action of the antibiotic colistin [10,11]. Here they review more generally the polymyxin and lipopeptide antibiotics, both of which act through some mechanism of membrane disruption, despite being structurally different [12]. These cyclic lipopeptides are not the most effective antibiotics and have toxicity issues that have limited their overall use in medicine.…”

Growth arrest ofStaphylococcus aureusinduces daptomycin tolerance via cell wall remodelling

“…The next objective was to determine which components of the cell surface were required for daptomycin tolerance. As changes to both the cell wall and membrane components of S. aureus have previously been associated with reduced daptomycin susceptibility [19,35,36,37,38,39,40,41,42], we tested each in turn, starting with membrane phospholipid synthesis.…”

“…Daptomycin targets phosphatidylglycerol (PG) and lipid II in the membrane, where it forms oligomeric complexes leading to membrane depolarisation and permeabilization [19,22,23,24]. The binding of daptomycin to lipid II also disrupts cell wall synthesis, which is further compromised by mis-localisation of enzymes involved in peptidoglycan synthesis [19,24,25,26].…”

“…One of the very few antibiotics reported to efficiently kill growth-arrested S. aureus is the lipopeptide daptomycin, which is used to treat infections caused by drug-resistant Gram-positive pathogens such as Methicillin Resistant Staphylococcus aureus (MRSA) [19,20,21]. Daptomycin targets phosphatidylglycerol (PG) and lipid II in the membrane, where it forms oligomeric complexes leading to membrane depolarisation and permeabilization [19,22,23,24]. The binding of daptomycin to lipid II also disrupts cell wall synthesis, which is further compromised by mis-localisation of enzymes involved in peptidoglycan synthesis [19,24,25,26].…”