Discovery of an antivirulence compound that reverses β-lactam resistance in MRSA Academic Article uri icon

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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.

authors

  • El-Halfawy, Omar M
  • Czarny, Tomasz L
  • Flannagan, Ronald S
  • Day, Jonathan
  • Bozelli, José Carlos
  • Kuiack, Robert C
  • Salim, Ahmed
  • Eckert, Philip
  • Epand, Richard
  • McGavin, Martin J
  • Organ, Michael G
  • Heinrichs, David E
  • Brown, Eric

publication date

  • February 2020

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