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

Katie N. Kang, Dustin R. Klein, Misha I. Kazi, François Guérin, Vincent Cattoir, Jennifer S. Brodbelt, Joseph M. Boll

Research output: Contribution to journalArticle

4 Citations (Scopus)

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, PhoPEclbinds to the arnBEcl promoter to induce l-Ara4N biosynthesis and PmrAB-independent addition to the lipid A disaccharolipid. Therefore, PhoPQEclcontributes to regulation of CAMP heteroresistance in some ECC clusters.

Original languageEnglish (US)
Pages (from-to)1604-1616
Number of pages13
JournalMolecular Microbiology
Volume111
Issue number6
DOIs
StatePublished - Jun 2019

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Colistin
Enterobacter cloacae
Lipid A
Antimicrobial Cationic Peptides
Enterobacteriaceae
Amines
Membranes
Microbiota
Multiple Drug Resistance
Cross Infection
4-amino-4-deoxyarabinose
Salmonella
Escherichia coli
Anti-Bacterial Agents
Bacteria

ASJC Scopus subject areas

  • Microbiology
  • Molecular Biology

Cite this

Colistin heteroresistance in Enterobacter cloacae is regulated by PhoPQ-dependent 4-amino-4-deoxy-l-arabinose addition to lipid A. / Kang, Katie N.; Klein, Dustin R.; Kazi, Misha I.; Guérin, François; Cattoir, Vincent; Brodbelt, Jennifer S.; Boll, Joseph M.

In: Molecular Microbiology, Vol. 111, No. 6, 06.2019, p. 1604-1616.

Research output: Contribution to journalArticle

Kang, Katie N. ; Klein, Dustin R. ; Kazi, Misha I. ; Guérin, François ; Cattoir, Vincent ; Brodbelt, Jennifer S. ; Boll, Joseph M. / Colistin heteroresistance in Enterobacter cloacae is regulated by PhoPQ-dependent 4-amino-4-deoxy-l-arabinose addition to lipid A. In: Molecular Microbiology. 2019 ; Vol. 111, No. 6. pp. 1604-1616.
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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, PhoPEclbinds to the arnBEcl promoter to induce l-Ara4N biosynthesis and PmrAB-independent addition to the lipid A disaccharolipid. Therefore, PhoPQEclcontributes to regulation of CAMP heteroresistance in some ECC clusters.",
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