Gallagher, LA, Shears, RK, Fingleton, C et al. (13 more authors) (2020) Impaired alanine transport or exposure to d-cycloserine increases the susceptibility of MRSA to β-lactam antibiotics. The Journal of Infectious Diseases, 221 (6). pp. 1000-1016. ISSN 0022-1899
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 re-sensitized MRSA to β-lactam antibiotics. The cycA mutation also resulted in hyper-susceptibility to DCS, an alanine analogue antibiotic that inhibits alanine racemase and d-alanine ligase required for d-alanine incorporation into cell wall peptidoglycan (PG). 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 PG crosslinking, prompting us to investigate synergism between β-lactams and DCS. DCS re-sensitised MRSA to β-lactams in vitro and significantly enhanced MRSA eradication by oxacillin in a mouse bacteraemia model. These findings reveal alanine transport as a new therapeutic target to enhance the susceptibility of MRSA to β-lactam antibiotics.</jats:p>
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. This is an author produced version of a paper published in The Journal of Infectious Diseases . Uploaded in accordance with the publisher's self-archiving policy. |
Dates: |
|
Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 06 Nov 2019 11:29 |
Last Modified: | 19 Oct 2020 00:40 |
Status: | Published |
Publisher: | Oxford University Press (OUP) |
Identification Number: | 10.1093/infdis/jiz542 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:153099 |