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Impaired Alanine Tr...
Impaired Alanine Transport or Exposure to D-Cycloserine Increases the Susceptibility of MRSA to beta-lactam Antibiotics
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Gallagher, Laura A. (author)
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Shears, Rebecca K. (author)
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Fingleton, Claire (author)
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- Alvarez, Laura (author)
- Umeå universitet,Molekylär Infektionsmedicin, Sverige (MIMS),Institutionen för molekylärbiologi (Medicinska fakulteten)
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Waters, Elaine M. (author)
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Clarke, Jenny (author)
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Bricio-Moreno, Laura (author)
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Campbell, Christopher (author)
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Yadav, Akhilesh K. (author)
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Razvi, Fareha (author)
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O'Neill, Eoghan (author)
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O'Neill, Alex J. (author)
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Cava, Felipe (author)
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Fey, Paul D. (author)
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Kadioglu, Aras (author)
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O'Gara, James P. (author)
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(creator_code:org_t)
- 2019-10-19
- 2020
- English.
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In: Journal of Infectious Diseases. - : OXFORD UNIV PRESS INC. - 0022-1899 .- 1537-6613. ; 221:6, s. 1006-1016
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https://www.ncbi.nlm...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- Prolonging the clinical effectiveness of beta-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 beta-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 beta-lactams and DCS. DCS resensitized MRSA to beta-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 beta-lactam antibiotics.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Infektionsmedicin (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Infectious Medicine (hsv//eng)
- NATURVETENSKAP -- Biologi -- Mikrobiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Microbiology (hsv//eng)
Keyword
- antibiotic resistance
- MRSA
- beta-lactam resistance
- alanine transport
- D-cycloserine
Publication and Content Type
- ref (subject category)
- art (subject category)
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Gallagher, Laura ...
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Shears, Rebecca ...
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Fingleton, Clair ...
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Alvarez, Laura
-
Waters, Elaine M ...
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Clarke, Jenny
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show more...
-
Bricio-Moreno, L ...
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Campbell, Christ ...
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Yadav, Akhilesh ...
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Razvi, Fareha
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O'Neill, Eoghan
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O'Neill, Alex J.
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Cava, Felipe
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Fey, Paul D.
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Kadioglu, Aras
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O'Gara, James P.
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show less...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Infectious Medic ...
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Microbiology
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Journal of Infec ...
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Umeå University