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

Abstract

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 cellmore » 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.« less

Authors:

de Carvalho, Carla C. C. R.  ^[1];

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Taglialegna, Agustina ^[2]; Rosato, Adriana E. ^[3]

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1. iBB-Institute for Bioengineering and Biosciences, Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
2. Department of Pathology and Genomic Medicine, Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Houston, TX, USA
3. Department of Pathology and Genomic Medicine, Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Houston, TX, USA, Department of Pathology and Molecular Microbiology Diagnostics-Research, Riverside University Health System, 26520 Cactus Avenue, Moreno Valley, CA 92555, USA, University of California, Riverside, CA, USA

Publication Date:

Thu Oct 07 00:00:00 EDT 2021

Sponsoring Org.:

USDOE Office of Nuclear Energy (NE), Nuclear Fuel Cycle and Supply Chain

OSTI Identifier:

1825131

Grant/Contract Number:  

UIDB/04565/2020; UIDP/04565/2020

Resource Type:

Published Article

Journal Name:

Journal of Antimicrobial Chemotherapy

Additional Journal Information:

Journal Name: Journal of Antimicrobial Chemotherapy; Journal ID: ISSN 0305-7453

Publisher:

Oxford University Press

Country of Publication:

United Kingdom

Language:

English