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Lookup NU author(s): Dr Jacob BiboyORCiD,
Professor Waldemar Vollmer
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© 2021 The AuthorsA major determinant of β-lactam resistance in methicillin-resistant Staphylococcus aureus (MRSA) is the drug insensitive transpeptidase, PBP2a, encoded by mecA. Full expression of the resistance phenotype requires auxiliary factors. Two such factors, auxiliary factor A (auxA, SAUSA300_0980) and B (auxB, SAUSA300_1003), were identified in a screen against mutants with increased susceptibility to β-lactams in the MRSA strain, JE2. auxA and auxB encode transmembrane proteins, with AuxA predicted to be a transporter. Inactivation of auxA or auxB enhanced β-lactam susceptibility in community-, hospital- and livestock-associated MRSA strains without affecting PBP2a expression, peptidoglycan cross-linking or wall teichoic acid synthesis. Both mutants displayed increased susceptibility to inhibitors of lipoteichoic acid (LTA) synthesis and alanylation pathways and released LTA even in the absence of β-lactams. The β-lactam susceptibility of the aux mutants was suppressed by mutations inactivating gdpP, which was previously found to allow growth of mutants lacking the lipoteichoic synthase enzyme, LtaS. Using the Galleria mellonella infection model, enhanced survival of larvae inoculated with either auxA or auxB mutants was observed compared with the wild-type strain following treatment with amoxicillin. These results indicate that AuxA and AuxB are central for LTA stability and potential inhibitors can be tools to re-sensitize MRSA strains to β-lactams and combat MRSA infections.
Author(s): Mikkelsen K, Sirisarn W, Alharbi O, Alharbi M, Liu H, Nohr-Meldgaard K, Mayer K, Vestergaard M, Gallagher LA, Derrick JP, McBain AJ, Biboy J, Vollmer W, O'Gara JP, Grunert T, Ingmer H, Xia G
Publication type: Article
Publication status: Published
Journal: International Journal of Antimicrobial Agents
Print publication date: 01/03/2021
Online publication date: 24/01/2021
Acceptance date: 19/12/2020
Date deposited: 08/04/2021
ISSN (print): 0924-8579
ISSN (electronic): 1872-7913
Publisher: Elsevier B.V.
PubMed id: 33503451
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