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Altered PBP4 and GdpP functions synergistically mediate MRSA-like high-level, broad-spectrum β-lactam resistance in Staphylococcus aureus

2024-03-26Artigo científico Acesso aberto
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dc.contributor.authorLai, Li Yin
dc.contributor.authorSatishkumar, Nidhi
dc.contributor.authorCardozo, Sasha
dc.contributor.authorHemmadi, Vijay
dc.contributor.authorMarques, Leonor B.
dc.contributor.authorHuang, Liusheng
dc.contributor.authorFilipe, Sergio R.
dc.contributor.authorPinho, Mariana G.
dc.contributor.authorChambers, Henry F.
dc.contributor.authorChatterjee, Som S.
dc.contributor.institutionInstituto de Tecnologia Química e Biológica António Xavier (ITQB)
dc.contributor.institutionFaculdade de Ciências e Tecnologia (FCT)
dc.contributor.pblAmerican Society for Microbiology
dc.date.accessioned2024-09-30T22:28:00Z
dc.date.available2024-09-30T22:28:00Z
dc.date.issued2024-03-26
dc.descriptionFunding Information: S.S.C. acknowledges the University of Maryland, Baltimore, and the University of Maryland Center for Environmental Science for providing seed funds. N.S. received Student Enhancement Funds from the Institute of Marine and Environmental Technology that partially covered travel expenses to Portugal for performing the cell wall analysis. L.B.M. was funded by fellowship UI/BD/153384/2022 from Funda\u00E7\u00E3o para a Ci\u00EAncia e a Tecnologia. Funding Information: Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award numbers R01AI165510 and 2R01AI100291 to SSC. The content is solely the responsibility of the authors and does not necessarily represent the views of the National Institutes of Health. Funding Information: National Institute of Allergy and R01AI165510 & Som S. Chatterjee Infectious Diseases 2R01AI100291 Publisher Copyright: Copyright © 2024 Lai et al.
dc.description.abstractInfections caused by Staphylococcus aureus are a leading cause of mortality worldwide. S. aureus infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are particularly difficult to treat due to their resistance to next-generation β-lactams (NGBs) such as methicillin, nafcillin, and oxacillin. Resistance to NGBs, which is alternatively known as broad-spectrum β-lactam resistance, is classically mediated by PBP2a, a penicillin-binding protein encoded by mecA (or mecC) in MRSA. Thus, presence of mec genes among S. aureus spp. serves as the predictor of resistance to NGBs and facilitates determination of the proper therapeutic strategy for a staphylococcal infection. Although far less appreciated, mecA-deficient S. aureus strains can also exhibit NGB resistance. These strains, which are collectively termed as methicillin-resistant lacking mec (MRLM), are currently being identified in increasing numbers among natural resistant isolates of S. aureus. The mechanism/s through which MRLMs produce resistance to NGBs remains unknown. In this study, we demonstrate that mutations that alter PBP4 and GdpP functions, which are often present among MRLMs, can synergistically mediate resistance to NGBs. Furthermore, our results unravel that this novel mechanism potentially enables MRLMs to produce resistance toward NGBs at levels comparable to those of MRSAs. Our study provides a fresh new perspective about alternative mechanisms of NGB resistance, challenging our current overall understanding of high-level, broad-spectrum β-lactam resistance in S. aureus. It thus suggests reconsideration of the current approach toward diagnosis and treatment of β-lactam-resistant S. aureus infections.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent4412122
dc.identifier.doi10.1128/mbio.02889-23
dc.identifier.issn2161-2129
dc.identifier.otherPURE: 98982736
dc.identifier.otherPURE UUID: 3b8bd5d6-d32e-40e9-975f-0b28e8c8b952
dc.identifier.otherScopus: 85192671240
dc.identifier.otherPubMed: 38530033
dc.identifier.urihttp://hdl.handle.net/10362/172696
dc.identifier.urlhttps://www.scopus.com/pages/publications/85192671240
dc.language.isoeng
dc.peerreviewedyes
dc.subjectgdpP
dc.subjectmethicillin-resistant lacking mec (MRLM)
dc.subjectpbp4
dc.subjectβ-lactam resistance
dc.subjectMicrobiology
dc.subjectVirology
dc.titleAltered PBP4 and GdpP functions synergistically mediate MRSA-like high-level, broad-spectrum β-lactam resistance in Staphylococcus aureusen
dc.typejournal article
degois.publication.issue5
degois.publication.titlemBio
degois.publication.volume15
dspace.entity.typePublication
rcaap.rightsopenAccess

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