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Mol Microbiol. 2019 Mar 15. doi: 10.1111/mmi.14240. [Epub ahead of print]

Colistin heteroresistance in Enterobacter cloacae is regulated by PhoPQ-dependent 4-amino-4-deoxy-l-arabinose addition to lipid A.

Author information

1
Department of Biology, University of Texas at Arlington, Arlington, TX, USA.
2
Department of Chemistry, University of Texas at Austin, Austin, TX, USA.
3
Department of Clinical Microbiology, Caen University Hospital, EA4655, University of Caen Normandie, Caen, France.
4
Department of Clinical Microbiology and National Reference Center for Antimicrobial Resistance (Lab Enterococci), Rennes University Hospital Inserm Unit U1230, University of Rennes 1, Rennes, France.

Abstract

The Enterobacter cloacae complex (ECC) consists of closely related bacteria commonly associated with the human microbiota. ECC are increasingly isolated from healthcare-associated infections, demonstrating that these Enterobacteriaceae are emerging nosocomial pathogens. ECC can rapidly acquire multidrug resistance to conventional antibiotics. Cationic antimicrobial peptides (CAMPs) have served as therapeutic alternatives because they target the highly conserved lipid A component of the Gram-negative outer membrane. Many Enterobacteriaceae fortify their outer membrane with cationic amine-containing moieties to prevent CAMP binding, which can lead to cell lysis. The PmrAB two-component system (TCS) directly activates 4-amino-4-deoxy-l-arabinose (l-Ara4N) biosynthesis to result in cationic amine moiety addition to lipid A in many Enterobacteriaceae such as E. coli and Salmonella. In contrast, PmrAB is dispensable for CAMP resistance in E. cloacae. Interestingly, some ECC clusters exhibit colistin heteroresistance, where a subpopulation of cells exhibit clinically significant resistance levels compared to the majority population. We demonstrate that E. cloacae lipid A is modified with l-Ara4N to induce CAMP heteroresistance and the regulatory mechanism is independent of the PmrABEcl TCS. Instead, PhoPEcl binds to the arnBEcl promoter to induce l-Ara4N biosynthesis and PmrAB-independent addition to the lipid A disaccharolipid. Therefore, PhoPQEcl contributes to regulation of CAMP heteroresistance in some ECC clusters.

PMID:
30873646
DOI:
10.1111/mmi.14240

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