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
  • 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. [email protected].
  • # 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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