Discovery of an Antivirulence Compound That Reverses β-lactam Resistance in MRSA

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2019 Nov 27

PMID 31768032

Citations 28

Authors

Omar M El-Halfawy

Tomasz L Czarny

Ronald S Flannagan

Jonathan Day

Jose Carlos Bozelli Jr

Robert C Kuiack

Ahmed Salim

Philip Eckert

Richard M Epand

Martin J McGavin

Michael G Organ

David E Heinrichs

Eric D Brown

Affiliations

Soon will be listed here.

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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