Two codependent routes lead to high-level MRSA
Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA), in which acquisition of <i>mecA</i> [which encodes the cell wall peptidoglycan biosynthesis component penicillin-binding protein 2a (PBP2a)] confers resistance to β-lactam antibiotics, is of major clinical concern. We show that, in the presence of antibiotics, MRSA adopts an alternative mode of cell division and shows an altered peptidoglycan architecture at the division septum. PBP2a can replace the transpeptidase activity of the endogenous and essential PBP2 but not that of PBP1, which is responsible for the distinctive native septal peptidoglycan architecture. Successful division without PBP1 activity requires the alternative division mode and is enabled by several possible chromosomal potentiator (<i>pot</i>) mutations. MRSA resensitizing agents differentially interfere with the two codependent mechanisms required for high-level antibiotic resistance, which provides opportunities for new interventions.
Authors
- Rebecca M. Corrigan (ORCID: https://orcid.org/0000-0002-6031-1148)
- Abimbola Feyisara Adedeji Olulana (ORCID: https://orcid.org/0000-0001-8009-1755)
- David S. Owen (ORCID: https://orcid.org/0000-0003-4989-8790)
- Laia Pasquina-Lemonche (ORCID: https://orcid.org/0000-0002-8592-9542)
- Sam Randerson (ORCID: https://orcid.org/0000-0001-7993-8218)
- Bohdan Bilyk (ORCID: https://orcid.org/0000-0003-4649-8492)
- Oliver J. Meacock (ORCID: https://orcid.org/0000-0001-6269-9855)
- Joshua A. F. Sutton (ORCID: https://orcid.org/0000-0002-0440-610X)
- Jeffrey Green (ORCID: https://orcid.org/0000-0002-9070-3361)
- James E. Florence
- William M. Durham (ORCID: https://orcid.org/0000-0002-8827-4705)
- D. Hornby (ORCID: https://orcid.org/0000-0002-8188-7023)
- Jamie K. Hobbs (ORCID: https://orcid.org/0000-0002-5872-1404)
- Simon J. Foster (ORCID: https://orcid.org/0000-0001-7432-7805)
- Lucía Lafage (ORCID: https://orcid.org/0000-0002-8105-5083)
- Katarzyna Wacnik (ORCID: https://orcid.org/0000-0002-9921-6746)
- Mariana Tinajero‐Trejo (ORCID: https://orcid.org/0000-0003-3444-7647)
- Sophie E. Irving (ORCID: https://orcid.org/0000-0003-0772-1946)
- Edward J. Beattie
- C. Ross (ORCID: https://orcid.org/0009-0002-5340-1601)
Institutions
- University College Dublin (IE)
- University of Sheffield (GB)
Publication Details
- Journal
- Science
- Published
- 2024-10-31
- DOI
- https://doi.org/10.1126/science.adn1369
- Citations
- 53
- Primary Topic
- Antimicrobial Resistance in Staphylococcus
- Type
- article
- Field-Weighted Citation Impact
- 20.62
Funders
- Wellcome Trust
- National Institute for Health and Care Research
- University of Galway
- Directorate for Biological Sciences
- Engineering and Physical Sciences Research Council
- Biotechnology and Biological Sciences Research Council