Identification of Evolutionary Trade-Offs Associated With High-Level Colistin Resistance in Acinetobacter baumannii
Kusumita Acharya1, Upasana Bhattacharya1, Shatarupa Biswas1
1AMR-Research Laboratory, Department of Biological Sciences, Adamas University, Kolkata, India.
Abstract:
Colistin (COL) belongs to the polymyxin group of drugs, which possesses a positive charge and interacts with lipopolysaccharide (LPS) of Gram-negative bacterial outer membranes. Acinetobacter baumannii, a bacterium in the "ESKAPE" group of "priority pathogens," has acquired resistance against the majority of available antibiotics, including the last resort antibiotic COL. Though plasmid-encoded acquisition of mcr-genes has been associated with clinical resistance, efflux, loss of LPS by inactivation of the biosynthetic pathway (lpxACD), and modifications of target LPS by products of chromosomal pmrCAB genes has been ascribed to resistance evolution. Systemic characterization of trade-offs and traits accompanying the evolution of COL resistance in the bacteria remains unaccomplished. Here we report adaptive evolution of extreme COL resistance of the reference strain A. baumannii ATCC19606. Systemic phenotypic characterization of the mutants revealed hyperbiofilm formation and a striking decrease in fitness as the major evolution-associated attributes. Comprehensive antibiotic susceptibility profiling indicated collateral sensitivity against vancomycin and fosfomycin. Whole genome sequencing of the resistant strains led to the identification of mutations associated with COL resistance. Phenotypic characterization of three COL-resistant clinical isolates of A. baumannii revealed similarity with experimentally evolved resistant mutants in one of the isolates, in which none of the mcr-genes could be detected.
Insights
Colistin resistance in Acinetobacter baumannii evolves with increased biofilm formation and decreased fitness. Resistant strains show collateral sensitivity to vancomycin and fosfomycin, offering potential therapeutic strategies.
Area of Science:
- Microbiology
- Bacterial Genetics
- Drug Resistance
Background:
- Colistin (COL) is a last-resort antibiotic against Gram-negative bacteria.
- Acinetobacter baumannii is a priority pathogen with increasing antibiotic resistance.
- Mechanisms of COL resistance include LPS modification and efflux, but trade-offs are poorly understood.
Purpose of the Study:
- To investigate the adaptive evolution of extreme colistin resistance in Acinetobacter baumannii.
- To characterize the phenotypic and genotypic changes associated with colistin resistance.
- To identify potential collateral sensitivities in colistin-resistant strains.
Main Methods:
- Adaptive laboratory evolution of Acinetobacter baumannii ATCC19606 to high colistin concentrations.
- Systemic phenotypic characterization, including biofilm formation and fitness assays.
- Antibiotic susceptibility profiling and whole-genome sequencing of evolved mutants.
- Phenotypic characterization of clinical colistin-resistant isolates.
Main Results:
- Evolved colistin-resistant mutants exhibited hyperbiofilm formation and significantly reduced bacterial fitness.
- Collateral sensitivity was observed against vancomycin and fosfomycin.
- Whole-genome sequencing identified mutations associated with colistin resistance.
- Clinical isolates showed resistance mechanisms similar to evolved strains, with no detected mcr-genes.
Conclusions:
- Colistin resistance evolution in Acinetobacter baumannii is accompanied by significant fitness costs and altered phenotypes.
- Collateral sensitivity presents potential alternative treatment options.
- Resistance mechanisms in clinical isolates may involve chromosomal alterations rather than plasmid-mediated mcr-genes.
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