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Metabolic reprogramming and altered cell envelope characteristics in a pentose phosphate pathway mutant increases MRSA resistance to β-lactam antibiotics
Microbiology, School of Biological and Chemical Sciences, University of Galway, Galway, Ireland.
Microbiology, School of Biological and Chemical Sciences, University of Galway, Galway, Ireland.
Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Microbiology, School of Biological and Chemical Sciences, University of Galway, Galway, Ireland.
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2023 (English)In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 19, no 7, article id e1011536Article in journal (Refereed) Published
Abstract [en]

Central metabolic pathways control virulence and antibiotic resistance, and constitute potential targets for antibacterial drugs. In Staphylococcus aureus the role of the pentose phosphate pathway (PPP) remains largely unexplored. Mutation of the 6-phosphogluconolactonase gene pgl, which encodes the only non-essential enzyme in the oxidative phase of the PPP, significantly increased MRSA resistance to β-lactam antibiotics, particularly in chemically defined media with physiologically-relevant concentrations of glucose, and reduced oxacillin (OX)-induced lysis. Expression of the methicillin-resistance penicillin binding protein 2a and peptidoglycan architecture were unaffected. Carbon tracing and metabolomics revealed extensive metabolic reprogramming in the pgl mutant including increased flux to glycolysis, the TCA cycle, and several cell envelope precursors, which was consistent with increased β-lactam resistance. Morphologically, pgl mutant cells were smaller than wild-type with a thicker cell wall and ruffled surface when grown in OX. The pgl mutation reduced resistance to Congo Red, sulfamethoxazole and oxidative stress, and increased resistance to targocil, fosfomycin and vancomycin. Levels of lipoteichoic acids (LTAs) were significantly reduced in pgl, which may limit cell lysis, while the surface charge of pgl cells was significantly more positive. A vraG mutation in pgl reversed the increased OX resistance phenotype, and partially restored wild-type surface charge, but not LTA levels. Mutations in vraF or graRS from the VraFG/GraRS complex that regulates DltABCD-mediated d-alanylation of teichoic acids (which in turn controls β-lactam resistance and surface charge), also restored wild-type OX susceptibility. Collectively these data show that reduced levels of LTAs and OX-induced lysis combined with a VraFG/GraRS-dependent increase in cell surface positive charge are accompanied by significantly increased OX resistance in an MRSA pgl mutant.

Place, publisher, year, edition, pages
Public Library of Science (PLoS), 2023. Vol. 19, no 7, article id e1011536
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Microbiology in the medical area
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URN: urn:nbn:se:umu:diva-212850DOI: 10.1371/journal.ppat.1011536ISI: 001037086000003PubMedID: 37486930Scopus ID: 2-s2.0-85166481432OAI: oai:DiVA.org:umu-212850DiVA, id: diva2:1787781
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Knut and Alice Wallenberg FoundationThe Kempe FoundationsAvailable from: 2023-08-15 Created: 2023-08-15 Last updated: 2023-08-15Bibliographically approved

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Bueno, EmilioCava, Felipe

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Molecular Infection Medicine Sweden (MIMS)Department of Molecular Biology (Faculty of Medicine)
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