Heteroresistance to Colistin in Klebsiella pneumoniae Associated with Alterations in the PhoPQ Regulatory System

Abstract

ABSTRACTA multidrug-resistantKlebsiella pneumoniaeisolate exhibiting heteroresistance to colistin was investigated. The colistin-resistant subpopulation harbored a single amino acid change (Asp191Tyr) in protein PhoP, which is part of the PhoPQ two-component system that activatespmrHFIJKLMexpression responsible forl-aminoarabinose synthesis and polymyxin resistance. Complementation assays with a wild-typephoPgene restored full susceptibility to colistin. Then, analysis of the colistin-susceptible subpopulation showed a partial deletion (25 bp) in thephoPgene compared to that in the colistin-resistant subpopulation. That deletion disrupted the reading frame ofphoP, leading to a longer and inactive protein (255 versus 223 amino acids long). This is the first report showing the involvement of mutation(s) in PhoP in colistin resistance. Furthermore, this is the first study to decipher the mechanisms leading to colistin heteroresistance inK. pneumoniae.