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IreB, a Ser/Thr kinase substrate, influences antimicrobial resistance in Enterococcus faecalis. Antimicrob Agents Chemother 2013 Dec;57(12):6179-86

Date

10/02/2013

Pubmed ID

24080657

Pubmed Central ID

PMC3837872

DOI

10.1128/AAC.01472-13

Scopus ID

2-s2.0-84887458824 (requires institutional sign-in at Scopus site)   51 Citations

Abstract

Enterococcus faecalis is a Gram-positive bacterium that is a major cause of hospital-acquired infections, in part due to its intrinsic resistance to cephalosporins. The mechanism that confers intrinsic cephalosporin resistance in enterococci remains incompletely defined. Previously, we have shown that the Ser/Thr protein kinase and phosphatase pair IreK and IreP act antagonistically to regulate cephalosporin resistance in E. faecalis. We hypothesize that IreK senses antibiotic-induced cell wall damage and activates a signaling pathway leading to antibiotic resistance. However, the factors downstream of IreK have not yet been identified. To discover such factors, suppressor mutations that restored resistance to a ΔireK kinase mutant were identified. Mutations were found in IreB, a highly conserved gene of unknown function that is widespread among low-GC Gram-positive bacteria. We show that IreB plays a negative regulatory role in cephalosporin resistance and is an endogenous substrate of both IreK and IreP. IreB is phosphorylated on conserved threonine residues, and mutations at these sites impair cephalosporin resistance. Our results are consistent with a model in which the activity of IreB is modulated by IreK-dependent phosphorylation in a signaling pathway required for cephalosporin resistance and begin to shed light on the function of this previously uncharacterized protein.

Author List

Hall CL, Tschannen M, Worthey EA, Kristich CJ

Author

Christopher J. Kristich PhD Professor in the Microbiology and Immunology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Anti-Bacterial Agents
Bacterial Proteins
Cephalosporin Resistance
Cephalosporins
Enterococcus faecalis
Gene Expression Regulation, Bacterial
Microbial Sensitivity Tests
Mutation
Phosphoric Monoester Hydrolases
Phosphorylation
Signal Transduction