Colistin Resistance Mechanisms in Gram-Negative Bacteria

Colistin, a polymyxin antibiotic rediscovered as a last-resort therapy against multidrug-resistant Gram-negative infections, exerts its bactericidal effect by binding to lipopolysaccharide (LPS) in the outer membrane and disrupting membrane integrity. Bacteria have evolved diverse strategies to evade this action. The most widespread mechanism involves chemical modification of lipid A, the membrane-anchored moiety of LPS, through addition of cationic moieties such as phosphoethanolamine or 4-amino-4-deoxy-L-arabinose. These modifications arise from mutations or upregulation of chromosomally encoded two-component regulatory systems (notably PhoPQ and PmrAB), which sense environmental cues and induce expression of lipid A–modifying enzymes. A parallel threat comes from plasmid-borne mobilised colistin resistance (mcr) genes, which encode phosphoethanolamine transferases able to disseminate rapidly among diverse species. Insertion sequences may disrupt the mgrB gene, a negative regulator of PhoPQ, leading to constitutive lipid A remodelling and high-level resistance. Additional contributors include overexpression of efflux pumps, changes in capsule production, and formation of heteroresistant subpopulations that harbour resistant variants within a susceptible culture. The interplay of chromosomal and mobile elements underscores the global challenge of preserving colistin efficacy. Understanding these pathways guides development of novel diagnostic markers, efflux inhibitors and combination therapies, as well as informs One Health interventions to curb the spread of resistance across clinical, agricultural and environmental settings.

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Colistin Resistance Mechanisms in Gram-Negative Bacteria publication trend

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

Technical terms

Lipopolysaccharide (LPS): A major component of the Gram-negative outer membrane that anchors lipid A and mediates interactions with colistin.

Lipid A: The membrane-bound glycolipid moiety of LPS that serves as the primary binding site for colistin.

mgrB: A small negative regulator of the PhoPQ two-component system whose inactivation leads to constitutive lipid A modification and resistance.

Insertion sequence (IS): A mobile DNA element capable of disrupting genes (for example, mgrB) and altering bacterial regulatory circuits.

Efflux pump: A membrane transporter that expels antibiotics from the cell, reducing intracellular drug concentration.

mcr genes: Plasmid-borne genes encoding phosphoethanolamine transferases that catalyse lipid A modification and confer transferable colistin resistance.

Heteroresistance: The presence of resistant subpopulations within a predominantly susceptible bacterial culture, often undetected by routine assays.

References

1. Colistin and its role in the Era of antibiotic resistance: an extended review (2000–2019). Emerging Microbes & Infections (2020).
2. Carbonyl Cyanide 3-Chloro Phenyl Hydrazone (CCCP) Restores the Colistin Sensitivity in Brucella intermedia. International Journal of Molecular Sciences (2023).
3. Within-host acquisition of colistin-resistance of an NDM-producing Klebsiella quasipneumoniae subsp. similipneumoniae strain through the insertion sequence-903B-mediated inactivation of mgrB gene in a lung transplant child in China. Frontiers in Cellular and Infection Microbiology (2023).
4. Heteroresistance to Colistin in Clinical Isolates of Klebsiella pneumoniae Producing OXA-48. Antibiotics (2023).