Dataset Information

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

ABSTRACT: Prolonging the clinical effectiveness of ?-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 ?-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 ?-lactams and DCS. DCS resensitized MRSA to ?-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 ?-lactam antibiotics.

SUBMITTER: Gallagher LA

PROVIDER: S-EPMC7050987 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Gallagher Laura A LA Shears Rebecca K RK Fingleton Claire C Alvarez Laura L Waters Elaine M EM Clarke Jenny J Bricio-Moreno Laura L Campbell Christopher C Yadav Akhilesh K AK Razvi Fareha F O'Neill Eoghan E O'Neill Alex J AJ Cava Felipe F Fey Paul D PD Kadioglu Aras A O'Gara James P JP

The Journal of infectious diseases 20200301 6

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 li ...[more]

PMID: 31628459

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Dataset Information

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

Publications

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

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