Impact of PrsA on membrane lipid composition during daptomycin-resistance-mediated β-lactam sensitization in clinical MRSA strains

Authors:
Open Access
Publisher website
Google Scholar
Abstract
Background: 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. Objectives: 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. Results: 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. Conclusions: 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.
Funding Information
  • Fundação para a Ciência e a Tecnologia, I.P. (FCT, Portugal) through programme ‘Investigador FCT 2013’ (IF/01203/ 2013/CP1163/CT0002)
  • FCT in the scope (UIDB/04565/2020, UIDP/04565/2020)
  • Research Unit iBB-Institute for Bioengineering and Biosciences
  • National Institutes of Health (NIH-R56AI102503-01A1)

This publication has 53 references indexed in Scilit: