Polymyxin Resistance Mechanisms in Gram-Negative Bacterial Infections

Polymyxins are last-resort antibiotics that target the outer membrane of Gram-negative pathogens by binding to lipid A, disrupting membrane integrity and causing cell death. The emergence of resistance to polymyxins threatens their clinical utility and stems from diverse mechanisms. Chromosomal mutations in two-component regulatory systems (such as PmrAB and PhoPQ) lead to modification of lipid A through addition of 4-amino-4-deoxy-L-arabinose or phosphoethanolamine, reducing drug binding. Plasmid-borne mcr genes encode phosphoethanolamine transferases that similarly alter lipid A and are readily transmissible between species. Loss or alteration of lipopolysaccharide (LPS) biosynthesis genes can result in LPS-deficient outer membranes that impede polymyxin action, while upregulation of efflux pumps and changes in membrane lipid composition further fortify bacterial defences. Metabolic remodelling and biofilm formation also contribute to tolerance by altering membrane fluidity and limiting antibiotic penetration. Combination therapies and adjuvant strategies are therefore under intense investigation to restore susceptibility and prevent resistance evolution.

Research from Nature Portfolio

A novel adjuvant approach has demonstrated that disulfiram, an alcohol-abuse drug, markedly potentiates polymyxin activity against strains expressing mobilized colistin resistance enzymes. Mechanistic studies reveal that disulfiram exacerbates polymyxin-induced membrane damage and disrupts bacterial metabolism, while minimising the emergence and transfer of resistance determinants. In vivo models confirm enhanced efficacy of the disulfiram–colistin combination against multidrug-resistant Gram-negative infections.

Foundational genomic and transcriptomic analyses of Acinetobacter baumannii exposed to clinically relevant polymyxin regimens have elucidated the emergence of stable resistance through mutations in pmrB and altered expression of genes involved in outer membrane biogenesis. Integrative data indicate that both chromosomal adaptation and reversible phenotypes contribute to heteroresistance, underscoring the need for optimised dosing and combination strategies to suppress resistant subpopulations.

Polymyxin Resistance Mechanisms in Gram-Negative Bacterial Infections publication trend

The graph below shows the total number of articles in polymyxin resistance mechanisms in gram-negative bacterial infections across all publications each year (not limited to Nature Index journals).

Technical terms

Polymyxins: Cationic cyclic peptides that disrupt the outer membrane of Gram-negative bacteria by binding to lipid A.

Lipopolysaccharide (LPS): An essential glycolipid forming the outer leaflet of the Gram-negative outer membrane, comprising lipid A, core oligosaccharide and O antigen.

Lipid A: The membrane-anchoring component of LPS, targeted by polymyxins and subject to chemical modification in resistant strains.

mcr genes: Mobile colistin resistance genes encoding enzymes that add phosphoethanolamine to lipid A, reducing polymyxin binding.

Adjuvant: A compound administered with an antibiotic to enhance its efficacy or prevent resistance development.

Two-component regulatory system: A bacterial signal transduction mechanism (e.g., PmrAB) that modulates gene expression in response to environmental stimuli, including antibiotic exposure.

References

1. Polysaccharide‐Targeting Lipid Nanoparticles to Kill Gram‐Negative Bacteria. Small (2023).
2. Resensitizing multidrug-resistant Gram-negative bacteria to carbapenems and colistin using disulfiram. Communications Biology (2023).
3. Drug Combination of Ciprofloxacin and Polymyxin B for the Treatment of Multidrug–Resistant Acinetobacter baumannii Infections: A Drug Pair Limiting the Development of Resistance. Pharmaceutics (2023).
4. Polymyxins and Bacterial Membranes: A Review of Antibacterial Activity and Mechanisms of Resistance. Membranes (2020).
5. Polymyxin Resistance in Acinetobacter baumannii: Genetic Mutations and Transcriptomic Changes in Response to Clinically Relevant Dosage Regimens. Scientific Reports (2016).