Impaired alanine transport or exposure to d-cycloserine increases the susceptibility of MRSA to β-lactam antibiotics.



Gallagher, Laura A, Shears, Rebecca K, Fingleton, Claire, Alvarez, Laura, Waters, Elaine M, Clarke, Jenny, Bricio-Moreno, Laura, Campbell, Christopher, Yadav, Akhilesh K, Razvi, Fareha
et al (show 6 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). 1000 - 1016.

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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.

Item Type: Article
Uncontrolled Keywords: antibiotic resistance, MRSA, β-lactam resistance, alanine transport, d-cycloserine
Depositing User: Symplectic Admin
Date Deposited: 04 Dec 2019 09:08
Last Modified: 23 Nov 2020 12:10
DOI: 10.1093/infdis/jiz542
Open Access URL: https://www.biorxiv.org/content/10.1101/616920v4
Related URLs:
URI: http://livrepository.liverpool.ac.uk/id/eprint/3063893