Renzoni, A.M., Kelley, W.L., Rosato, R.R. et al. (9 more authors) (2017) Molecular bases determining daptomycin resistance-mediated re-sensitization to β-lactams ("see-saw effect") in MRSA. Antimicrobial Agents and Chemotherapy, 61 (1). e01634-16. ISSN 0066-4804
Abstract
Antimicrobial resistance is recognized as one of the principal threats to public health worldwide, yet the problem is increasing. Methicillin-resistant Staphylococcus aureus (MRSA) are among the most difficult to treat in clinical settings due to the resistance to nearly all available antibiotics. The cyclic anionic lipopeptide antibiotic Daptomycin (DAP) is the clinical mainstay of anti-MRSA therapy. Decreased susceptibility to DAP (DAPR) reported in MRSA is frequently accompanied with a paradoxical decrease in β-lactam resistance, a process known as the "see-saw" effect. Despite the observed discordance in resistance phenotypes, the combination of DAP/β-lactams has been proven clinically effective for the prevention and treatment of infections due to DAPR-MRSA strains. However, the mechanisms underlying the interactions between DAP and β-lactams are largely unknown. Herein, we studied the role of DAP-induced mutated mprF in β-lactam sensitization and its involvement in the effective killing by the DAP/OXA combination. DAP/OXA-mediated effects resulted in cell-wall perturbations including changes in peptidoglycan (PG) insertion, penicillin-binding protein 2 (PBP2) delocalization and reduced membrane amounts of penicillin-binding protein 2a (PBP2a) contents despite increased transcription of mecA through mec regulatory elements. We have found that the VraSR sensor-regulator is a key component of DAP resistance, triggering mutated mprF-mediated cell membrane (CM) modifications and resulting in impairment of PrsA location and chaperone functions, both essentials for PBP2a maturation, the key determinant of β-lactam resistance. These observations provide first time evidence that synergistic effects between DAP and β-lactams involve PrsA post-transcriptional regulation of CM-associated PBP2a.
Metadata
Item Type: | Article |
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Authors/Creators: | This paper has 12 authors. You can scroll the list below to see them all or them all.
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Copyright, Publisher and Additional Information: | © 2016 American Society for Microbiology. This is an author produced version of a paper subsequently published in Antimicrobial Agents and Chemotherapy. Uploaded in accordance with the publisher's self-archiving policy. |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) > Department of Molecular Biology and Biotechnology (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 30 Nov 2016 12:41 |
Last Modified: | 29 Jan 2018 10:55 |
Published Version: | https://doi.org/10.1128/AAC.01634-16 |
Status: | Published |
Publisher: | American Society for Microbiology |
Refereed: | Yes |
Identification Number: | 10.1128/AAC.01634-16 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:108640 |