2. Academic Validation
  3. Restoring susceptibility to β-lactam antibiotics in methicillin-resistant Staphylococcus aureus

Restoring susceptibility to β-lactam antibiotics in methicillin-resistant Staphylococcus aureus

  • Nat Chem Biol. 2024 Jul 26. doi: 10.1038/s41589-024-01688-0.
Van T Nguyen 1,  Biruk T Birhanu # 1,  Vega Miguel-Ruano # 2,  Choon Kim 1,  Mayte Batuecas 2,  Jingdong Yang 1,  Amr M El-Araby 1,  Eva Jiménez-Faraco 2,  Valerie A Schroeder 1,  Alejandra Alba 2,  Neha Rana 1,  Safaa Sader 1,  Caitlyn A Thomas 1,  Rhona Feltzer 1,  Mijoon Lee 1,  Jed F Fisher 1,  Juan A Hermoso 2,  Mayland Chang 1,  Shahriar Mobashery 3
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA.
  • 2 Department of Crystallography and Structural Biology, Instituto de Química-Física 'Blas Cabrera', Consejo Superior de Investigaciones Científicas, Madrid, Spain.
  • 3 Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA. mobashery@nd.edu.
  • # Contributed equally.
PMID: 39060390 DOI: 10.1038/s41589-024-01688-0
Abstract

Infections by Staphylococcus aureus have been treated historically with β-lactam Antibiotics. However, these Antibiotics have become obsolete in methicillin-resistant S. aureus by acquisition of the bla and mec operons. The presence of the β-lactam Antibiotic is detected by the sensor domains of BlaR and/or MecR, and the information is transmitted to the cytoplasm, resulting in derepression of the antibiotic-resistance genes. We hypothesized that inhibition of the sensor domain would shut down this response system, and β-lactam susceptibility would be restored. An in silico search of 11 million compounds led to a benzimidazole-based hit and, ultimately, to the boronate 4. The X-ray structure of 4 is covalently engaged with the active-site serine of BlaR. Compound 4 potentiates by 16- to 4,096-fold the activities of oxacillin and of meropenem against methicillin-resistant S. aureus strains. The combination of 4 with oxacillin or meropenem shows efficacy in infected mice, validating the strategy.

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