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Colistin Heteroresistance and Involvement of the PmrAB Regulatory System in Acinetobacter baumannii
Yannick Charretier1, Seydina M Diene2, Damien Baud2
1Genomic Research Laboratory, Service of Infectious Diseases, Geneva University Hospitals, Geneva, Switzerland yannick.charretier@genomic.ch.
Abstract:
Multidrug-resistant Acinetobacter baumannii infection has recently emerged as a worldwide clinical problem, and colistin is increasingly being used as a last-resort therapy. Despite its favorable bacterial killing, resistance and heteroresistance (HR) to colistin have been described. The purpose of the present study was to investigate the role of the PmrAB regulatory pathway in laboratory-selected mutants representative of global epidemic strains. From three unrelated A. baumannii clinical strains (sequence types 2, 3, and 20), eight colistin-resistant mutants were selected. Half of the mutants showed HR to colistin according to the reference method (population analysis profiling), whereas the other half exhibited stable resistance. M12I mutation within pmrA and M308R, S144KLAGS, and P170L mutations for pmrB were associated with HR to colistin, while T235I, A226T, and P233S mutations within pmrB were associated with stable resistance. The transcript levels of the pmrCAB operon were upregulated in all the mutants. Compensatory mutations were explored for some mutants. A single mutant (T235I mutant) displayed a compensatory mutation through ISAba1 mobilization within the pmrB gene that was associated with the loss of colistin resistance. The mutant resistance phenotype associated with T235I was partially restored in a trans-complementation assay turning to HR. The level of colistin resistance was correlated with the level of expression of pmrC in the trans-complemented strains. This report shows the role of different mutations in the PmrAB regulatory pathway and warns of the development of colistin HR that could be present but not easily detected through routine testing.
Insights
Multidrug-resistant Acinetobacter baumannii can develop resistance to colistin, a last-resort antibiotic. Mutations in the PmrAB pathway cause stable resistance or heteroresistance (HR), which may go undetected in standard tests.
Area of Science:
- Microbiology
- Genetics
- Antimicrobial Resistance
Background:
- Multidrug-resistant Acinetobacter baumannii poses a global health threat.
- Colistin is a critical last-resort antibiotic for treating A. baumannii infections.
- Emerging resistance and heteroresistance (HR) to colistin are significant clinical concerns.
Purpose of the Study:
- To investigate the PmrAB regulatory pathway's role in laboratory-selected colistin-resistant Acinetobacter baumannii mutants.
- To characterize mutations associated with stable resistance versus heteroresistance (HR) to colistin.
- To explore compensatory mutations and their impact on colistin resistance.
Main Methods:
- Selection of eight colistin-resistant mutants from three unrelated A. baumannii clinical strains (STs 2, 3, and 20).
- Population analysis profiling (PAP) to distinguish between stable resistance and heteroresistance (HR).
- Sequencing of PmrAB pathway genes and transcript level analysis of the pmrCAB operon.
- Trans-complementation assays to assess the impact of specific mutations.
Main Results:
- Mutations in pmrA (M12I) and pmrB (M308R, S144KLAGS, P170L) were associated with colistin heteroresistance (HR).
- Mutations in pmrB (T235I, A226T, P233S) were associated with stable colistin resistance.
- All mutants showed upregulated pmrCAB operon transcript levels.
- A compensatory mutation (ISaba1 mobilization) in the T235I mutant led to loss of resistance, which could be partially restored to HR via trans-complementation.
Conclusions:
- Specific mutations within the PmrAB pathway dictate either stable colistin resistance or heteroresistance (HR) in A. baumannii.
- Colistin heteroresistance (HR) may be underestimated by standard antimicrobial susceptibility testing.
- Understanding these resistance mechanisms is crucial for effective treatment strategies against multidrug-resistant A. baumannii.
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