MgrB Inactivation Is a Common Mechanism of Colistin Resistance in KPC-Producing Klebsiella pneumoniae of Clinical Origin

Abstract

ABSTRACTKlebsiella pneumoniaestrains producing KPC-type carbapenemases (KPC-KP) are challenging multidrug-resistant pathogens due to their extensively drug-resistant phenotypes and potential for epidemic dissemination in health care settings. Colistin is a key component of the combination antimicrobial regimens used for treatment of severe KPC-KP infections. We previously reported that insertional inactivation of themgrBgene, encoding a negative-feedback regulator of the PhoQ-PhoP signaling system, can be responsible for colistin resistance in KPC-KP, due to the resulting upregulation of the Pmr lipopolysaccharide modification system. In this work we investigated the status of themgrBgene in a collection of 66 colistin-resistant nonreplicate clinical strains of KPC-KP isolated from different hospitals in Italy and Greece. Overall, 35 strains (53%) exhibited alterations of themgrBgene, including insertions of different types of mobile elements (IS5-like, IS1F-like, or ISKpn14), nonsilent point mutations, and small intragenic deletions. Four additional strains had a larger deletion of themgrBlocus, while the remaining 27 strains (41%) did not showmgrBalterations. Transcriptional upregulation of thephoQandpmrKgenes (part of thephoPQandpmrHFIJKLMoperon, respectively) was observed in all strains withmgrBalterations. Complementation experiments with a wild-typemgrBgene restored colistin susceptibility and basal expression levels ofphoQandpmrKgenes in strains carrying different types ofmgrBalterations. The present results suggest thatmgrBalteration can be a common mechanism of colistin resistance among KPC-KP in the clinical setting.