| Autor: |
Lai LY; Department of Microbial Pathogenesis, School of Dentistry, University of Maryland Baltimore, USA.; Institute of Marine and Environmental Technology (IMET), Baltimore, USA., Satishkumar N; Department of Microbial Pathogenesis, School of Dentistry, University of Maryland Baltimore, USA.; Institute of Marine and Environmental Technology (IMET), Baltimore, USA., Cardozo S; Department of Microbial Pathogenesis, School of Dentistry, University of Maryland Baltimore, USA.; Institute of Marine and Environmental Technology (IMET), Baltimore, USA., Hemmadi V; Department of Microbial Pathogenesis, School of Dentistry, University of Maryland Baltimore, USA.; Institute of Marine and Environmental Technology (IMET), Baltimore, USA., Marques LB; Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal., Huang L; Drug Research Unit, Department of Clinical Pharmacy, University of California, San Francisco, San Francisco, CA, USA., Filipe SR; Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal.; UCIBIO-REQUIMTE, Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Caparica, Portugal., Pinho MG; Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa, Oeiras, Portugal., Chambers HF; Division of Infectious Diseases, School of Medicine, University of California San Francisco, San Francisco, CA, USA., Chatterjee SS; Department of Microbial Pathogenesis, School of Dentistry, University of Maryland Baltimore, USA.; Institute of Marine and Environmental Technology (IMET), Baltimore, USA. |
| Abstrakt: |
Infections 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 (NGB) such as Methicillin, Nafcillin, Oxacillin etc. 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 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 towards NGBs at levels comparable to that of MRSAs. Our study, provides a fresh new perspective about alternative mechanisms of NGBs 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 towards diagnosis and treatment of β-lactam resistant S. aureus infections. |
