Open AccessImpaired Alanine Transport or Exposure to d-Cycloserine Increases the Susceptibility of MRSA to β-lactam Antibiotics
Author(s) -
Laura A. Gallagher,
Rebecca K. Shears,
Claire Fingleton,
Laura Álvarez,
Elaine M. Waters,
Jenny Clarke,
Laura Bricio-Moreno,
Christopher Campbell,
Aparna Yadav,
Fareha Razvi,
Eoghan O’Neill,
Alex J. O’Neill,
Felipe Cava,
Paul D. Fey,
Aras Kadioglu,
James P. O’Gara
Publication year - 2019
Publication title -
the journal of infectious diseases (online. university of chicago press)/the journal of infectious diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.69
H-Index - 252
eISSN - 1537-6613
pISSN - 0022-1899
DOI - 10.1093/infdis/jiz542
Subject(s) - peptidoglycan , antibiotics , microbiology and biotechnology , alanine , tripeptide , cycloserine , nafcillin , staphylococcus aureus , mutant , chemistry , biology , biochemistry , penicillin , bacteria , peptide , gene , amino acid , genetics
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.