Impaired Alanine Transport or Exposure to d-Cycloserine Increases the Susceptibility of MRSA to β-lactam Antibiotics

Laura A. Gallagher, Rebecca K. Shears, Claire Fingleton, Laura Alvarez, Elaine M. Waters, Jenny Clarke, Laura Bricio-Moreno, Christopher Campbell, Akhilesh K. Yadav, Fareha Razvi, Eoghan O'Neill, Alex J. O'Neill, Felipe Cava, Paul D. Fey, Aras Kadioglu, James P. O'Gara

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Prolonging the clinical effectiveness of β-lactams, which remain first-line antibiotics for many infections, is an important part of efforts to address antimicrobial resistance. We report here that inactivation of the predicted d-cycloserine (DCS) transporter gene cycA resensitized methicillin-resistant Staphylococcus aureus (MRSA) to β-lactam antibiotics. The cycA mutation also resulted in hypersusceptibility to DCS, an alanine analogue antibiotic that inhibits alanine racemase and d-alanine ligase required for d-alanine incorporation into cell wall peptidoglycan. Alanine transport was impaired in the cycA mutant, and this correlated with increased susceptibility to oxacillin and DCS. The cycA mutation or exposure to DCS were both associated with the accumulation of muropeptides with tripeptide stems lacking the terminal d-ala-d-ala and reduced peptidoglycan cross-linking, prompting us to investigate synergism between β-lactams and DCS. DCS resensitized MRSA to β-lactams in vitro and significantly enhanced MRSA eradication by oxacillin in a mouse bacteremia model. These findings reveal alanine transport as a new therapeutic target to enhance the susceptibility of MRSA to β-lactam antibiotics.

Original languageEnglish (US)
Pages (from-to)1006-1016
Number of pages11
JournalJournal of Infectious Diseases
Volume221
Issue number6
DOIs
StatePublished - Mar 15 2020

Keywords

  • Alanine transport
  • Antibiotic resistance
  • D-cycloserine
  • MRSA
  • β-lactam resistance

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

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