Colistin heteroresistance and the involvement of the PmrAB regulatory system in Acinetobacter baumannii [PublishAheadOfPrint]

Multidrug-resistant Acinetobacter baumannii infection has recently emerged as a worldwide clinical problem and colistin is increasingly being used for last resort therapy. Despite its favorable bacterial killing, resistance and heteroresistance (HR) to colistin have been described. The purpose of the present study is 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 Type 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 transcripts levels of the pmrCAB operon were upregulated in all the mutants. Compensatory mutations were explored for some mutants. A single mutant (T235I) 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 is 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 on the development of colistin HR that could be present but not easily detected through routine testing.

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