Discovery of an antivirulence compound that reverses β-lactam resistance in MRSA

  • Nat Chem Biol. 2020 Feb;16(2):143-149. doi: 10.1038/s41589-019-0401-8.
Omar M El-Halfawy  1  2  3 ,  Tomasz L Czarny  1  2 ,  Ronald S Flannagan  4 ,  Jonathan Day  5 ,  José Carlos Bozelli Jr  1 ,  Robert C Kuiack  4 ,  Ahmed Salim  5 ,  Philip Eckert  6 ,  Richard M Epand  1 ,  Martin J McGavin  4 ,  Michael G Organ  5  6 ,  David E Heinrichs  4 ,  Eric D Brown  7  8
Affiliations
  • 1. Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
  • 2. Michael G. DeGroote Institute of Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
  • 3. Microbiology and Immunology Department, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
  • 4. Department of Microbiology and Immunology, The University of Western Ontario, London, Ontario, Canada.
  • 5. Department of Chemistry, York University, Toronto, Ontario, Canada.
  • 6. Centre for Catalysis Research and Innovation (CCRI) and Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Ontario, Canada.
  • 7. Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada. [email protected].
  • 8. Michael G. DeGroote Institute of Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada. [email protected].
PMID: 31768032 DOI: 10.1038/s41589-019-0401-8
Abstract

Staphylococcus aureus is the leading cause of infections worldwide, and methicillin-resistant strains (MRSA) are emerging. New strategies are urgently needed to overcome this threat. Using a cell-based screen of ~45,000 diverse synthetic compounds, we discovered a potent bioactive, MAC-545496, that reverses β-lactam resistance in the community-acquired MRSA USA300 strain. MAC-545496 could also serve as an antivirulence agent alone; it attenuates MRSA virulence in Galleria mellonella larvae. MAC-545496 inhibits biofilm formation and abrogates intracellular survival in macrophages. Mechanistic characterization revealed MAC-545496 to be a nanomolar inhibitor of GraR, a regulator that responds to cell-envelope stress and is an important virulence factor and determinant of Antibiotic resistance. The small molecule discovered herein is an inhibitor of GraR function. MAC-545496 has value as a research tool to probe the GraXRS regulatory system and as an Antibacterial lead series of a mechanism to combat drug-resistant Staphylococcal infections.

Products