Colistin Resistance Mechanisms in Acinetobacter baumannii

Acinetobacter baumannii has emerged as a critical challenge in healthcare settings owing to its capacity to withstand most antibacterial agents. Colistin, a cationic lipopeptide antibiotic, acts by binding to lipid A of lipopolysaccharide in the bacterial outer membrane, disrupting membrane integrity and causing cell death. Resistance to colistin in A. baumannii arises predominantly through chromosomal mutations or acquisition of mobile elements that alter or eliminate the drug’s target. Inactivation of the lpxACD operon leads to complete loss of lipopolysaccharide, preventing colistin binding. Alternatively, the pmrCAB two-component regulatory system and eptA-encoded phosphoethanolamine transferases mediate the addition of phosphoethanolamine moieties to lipid A, reducing colistin affinity. Plasmid-borne mcr genes provide a further conduit for resistance dissemination. Efflux mechanisms and outer-membrane remodelling complement these modifications, while heteroresistance—coexistence of susceptible and resistant subpopulations—complicates treatment outcomes. Resistance mutations often incur fitness or virulence costs, yet compensatory changes may restore bacterial fitness, facilitating spread of resistant clones. Global surveillance underscores biogeographical variation in resistance rates, with certain international lineages demonstrating persistent colistin susceptibility despite carrying polymorphisms in known resistance operons. As colistin represents a last-resort therapy against multidrug-resistant A. baumannii, understanding these diverse resistance pathways is pivotal for informing stewardship and guiding development of adjuvant therapies.

Research from Nature Portfolio

Studies have demonstrated that targeting bacterial iron homeostasis can dramatically enhance colistin efficacy. A phytochemical, when co-administered with sub-inhibitory colistin, induces iron dysregulation, provoking a lethal surge of reactive oxygen species that overcomes both intrinsic and acquired resistance in clinical A. baumannii strains. This proof-of-principle offers a strategic template for adjuvant development against resistant infections. In foundational work, spontaneous colistin-resistant mutants were generated and subjected to whole-genome sequencing, revealing novel mutations in lpxACD and pmrB as well as in previously unrecognised loci implicated in membrane integrity. These findings highlight the rapidity with which A. baumannii can evolve under colistin pressure and underscore the necessity for real-time genomic surveillance to detect emerging resistance determinants.

Colistin Resistance Mechanisms in Acinetobacter baumannii publication trend

The graph below shows the total number of articles in colistin resistance mechanisms in acinetobacter baumannii across all publications each year (not limited to Nature Index journals).

Technical terms

Lipopolysaccharide (LPS): A complex glycolipid in the outer membrane of Gram-negative bacteria, consisting of lipid A, a core oligosaccharide and an O-antigen.

Phosphoethanolamine (PEtN) transferase: An enzyme that modifies lipid A by adding phosphoethanolamine, reducing colistin binding.

Two-component system: A paired sensor kinase and response regulator that modulate gene expression in response to environmental stimuli, exemplified by PmrAB.

Temperate bacteriophage: A virus that can integrate into the bacterial chromosome and later enter lytic or lysogenic cycles, potentially mobilising resistance genes.

Minimal inhibitory concentration (MIC): The lowest concentration of an antimicrobial required to prevent visible growth of a microorganism under defined conditions.

References

1. Phage-mediated colistin resistance in Acinetobacter baumannii. Drug Resistance Updates (2024).
2. Disrupting iron homeostasis can potentiate colistin activity and overcome colistin resistance mechanisms in Gram-Negative Bacteria. Communications Biology (2023).
3. Diclofenac sensitizes multi-drug resistant Acinetobacter baumannii to colistin. PLOS Pathogens (2024).
4. Retained colistin susceptibility in clinical Acinetobacter baumannii isolates with multiple mutations in pmrCAB and lpxACD operons. Frontiers in Cellular and Infection Microbiology (2023).
5. Colistin Resistance in Acinetobacter baumannii: Molecular Mechanisms and Epidemiology. Antibiotics (2023).
6. Prevalence of colistin resistance in clinical isolates of Acinetobacter baumannii: a systematic review and meta-analysis. Antimicrobial Resistance & Infection Control (2024).
7. The induction and identification of novel Colistin resistance mutations in Acinetobacter baumannii and their implications. Scientific Reports (2016).
8. Interplay between Colistin Resistance, Virulence and Fitness in Acinetobacter baumannii. Antibiotics (2017).