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Updated: Sep 20, 2025

Testing the Role of Multicopy Plasmids in the Evolution of Antibiotic Resistance
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Localized pmrB hypermutation drives the evolution of colistin heteroresistance

Natalia Kapel1, Julio Diaz Caballero1, R Craig MacLean1

  • 1University of Oxford, Department of Zoology, 11a Mansfield Road, Oxford OX1 3SZ, UK.

Cell Reports
|June 8, 2022
PubMed

Insights

Colistin resistance in Pseudomonas aeruginosa is poorly understood. This study reveals that rapid evolution of colistin resistance occurs through mutations in the PmrAB system, potentially as an adaptation to host immunity.

Area of Science:

  • Microbiology
  • Genetics
  • Evolutionary Biology

Background:

  • Colistin is a critical last-resort antibiotic for treating multidrug-resistant (MDR) Gram-negative bacterial infections.
  • Understanding the mechanisms of colistin resistance is crucial for combating challenging infections.

Purpose of the Study:

  • To investigate the evolutionary responses of Pseudomonas aeruginosa to high-dose colistin exposure.
  • To identify the genetic basis and mechanisms driving colistin heteroresistance.

Main Methods:

  • Exposure of approximately 1,000 populations of an MDR P. aeruginosa strain to high colistin concentrations.
  • Analysis of genetic mutations, particularly in the PmrAB regulatory system, associated with colistin resistance.
  • Assessment of the stability of colistin resistance under different culture conditions.

Main Results:

  • Colistin exposure led to rapid cell death, followed by recovery due to the emergence of heteroresistant subpopulations.
  • Colistin heteroresistance was unstable and rapidly lost in the absence of colistin.
  • Evolution of resistance was primarily driven by selection at two hotspot sites in the PmrAB system, with localized hypermutation of pmrB increasing resistance mutation rates significantly.
  • The PmrAB system confers resistance to antimicrobial peptides involved in host immunity.

Conclusions:

  • The PmrAB system is a key driver of colistin heteroresistance in P. aeruginosa.
  • The rapid evolution and instability of colistin resistance suggest a dynamic adaptation process.
  • A highly mutable pmrB may represent an evolutionary adaptation of P. aeruginosa to host immune pressures.
Keywords:
AMRCP: MicrobiologyPseudomonas aeruginosaantibiotic resistancecolistinevolutionary rescueexperimental evolutionheteroresistancehypermutabilitymutation rate

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