2. Academic Validation
  3. Discovery of an antivirulence compound that reverses β-lactam resistance in MRSA

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

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. ebrown@mcmaster.ca.
  • 8 Michael G. DeGroote Institute of Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada. ebrown@mcmaster.ca.
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.

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