Accumulation of succinyl coenzyme a perturbs the methicillin-resistant staphylococcus aureus (Mrsa) succinylome and is associated with increased susceptibility to beta-lactam antibiotics

Christopher Campbell, Claire Fingleton, Merve S. Zeden, Emilio Bueno, Laura A. Gallagher, Dhananjay Shinde, Jongsam Ahn, Heather M. Olson, Thomas L. Fillmore, Joshua N. Adkins, Fareha Razvi, Kenneth W. Bayles, Paul D. Fey, Vinai C. Thomas, Felipe Cava, Geremy C. Clair, James P. O’gara

Research output: Contribution to journalArticlepeer-review

Abstract

Penicillin binding protein 2a (PBP2a)-dependent resistance to β-lactam antibiotics in methicillin-resistant Staphylococcus aureus (MRSA) is regulated by the activity of the tricarboxylic acid (TCA) cycle via a poorly understood mechanism. We report that mutations in sucC and sucD, but not other TCA cycle enzymes, negatively impact β-lactam resistance without changing PBP2a expression. Increased intracellular levels of succinyl coenzyme A (succinyl-CoA) in the sucC mutant significantly perturbed lysine succinylation in the MRSA proteome. Suppressor mutations in sucA or sucB, responsible for succinyl-CoA biosynthesis, reversed sucC mutant phenotypes. The major autolysin (Atl) was the most succinylated protein in the proteome, and increased Atl succinylation in the sucC mutant was associated with loss of autolytic activity. Although PBP2a and PBP2 were also among the most succinylated proteins in the MRSA proteome, peptidoglycan architecture and cross-linking were unchanged in the sucC mutant. These data reveal that perturbation of the MRSA succinylome impacts two interconnected cell wall phenotypes, leading to repression of autolytic activity and increased susceptibility to β-lactam antibiotics.

Original languageEnglish (US)
Article numbere00530-21
JournalmBio
Volume12
Issue number3
DOIs
StatePublished - Jun 2021

Keywords

  • Antibiotic resistance
  • Beta-lactams
  • MRSA
  • Succinyl-CoA
  • Succinylome
  • TCA cycle

ASJC Scopus subject areas

  • Microbiology
  • Virology

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