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- Title
Impact of PrsA on membrane lipid composition during daptomycin-resistance-mediated β-lactam sensitization in clinical MRSA strains.
- Authors
Carvalho, Carla C C R de; Taglialegna, Agustina; Rosato, Adriana E; de Carvalho, Carla C C R
- Abstract
<bold>Background: </bold>The cyclic anionic lipopeptide daptomycin is used in the treatment of severe infections caused by Gram-positive pathogens, including MRSA. Daptomycin resistance, although rare, often results in treatment failure. Paradoxically, in MRSA, daptomycin resistance is usually accompanied by a concomitant decrease in β-lactam resistance in what is known as the 'see-saw effect'. This resensitization is extensively used for the treatment of MRSA infections, by combining daptomycin and a β-lactam antibiotic, such as oxacillin.<bold>Objectives: </bold>We aimed: (i) to investigate the combined effects of daptomycin and oxacillin on the lipid composition of the cellular membrane of both daptomycin-resistant and -susceptible MRSA strains; and (ii) to assess the involvement of the post-translocational protein PrsA, which plays an important role in oxacillin resistance in MRSA, in membrane lipid composition and remodelling during daptomycin resistance/β-lactam sensitization.<bold>Results: </bold>The combination of microbiological and biochemical studies, with fluorescence microscopy using lipid probes, showed that the lipid composition and surface charge of the daptomycin-resistant cells exposed to daptomycin/oxacillin were dependent on antibiotic concentration and directly associated with PrsA, which influenced cardiolipin remodelling/relocation.<bold>Conclusions: </bold>Our findings show that PrsA, in addition to its post-transcriptional role in the maturation of PBP 2a, is a key mediator of cell membrane remodelling connected to the see-saw effect and may have a key role in the resensitization of daptomycin-resistant strains to β-lactams, such as oxacillin.
- Subjects
BETA lactam antibiotics; MEMBRANE lipids; ANTIBIOTICS; METHICILLIN-resistant staphylococcus aureus; DAPTOMYCIN; SURFACE charges; FLUORESCENCE microscopy; LIPID metabolism; RESEARCH; OXACILLIN; EVALUATION research; STAPHYLOCOCCAL diseases; COMPARATIVE studies; IMPACT of Event Scale; RESEARCH funding; LIPIDS; MICROBIAL sensitivity tests; PHARMACODYNAMICS
- Publication
Journal of Antimicrobial Chemotherapy (JAC), 2022, Vol 77, Issue 1, p135
- ISSN
0305-7453
- Publication type
journal article
- DOI
10.1093/jac/dkab356