MAC-545496

MAC-545496 is a nanomolar inhibitor of glycopeptide-resistance-associated protein R (GraR). MAC-545496 displays strong binding affinity to the full-length GraR protein (Kd ≤ 0.1 nM). MAC-545496 is an antivirulence agent that reverses β-lactam resistance in Methicillin-resistant strains (MRSA)[1].

Research Areas >> Infection

Signaling Pathways >> Anti-infection >> Bacterial

Glycopeptide-resistance-associated protein R (GraR)[1]

MAC-545496 potently synergizes with Cefuroxime; concentrations as low as 0.03 µg/mL (~75 nM) lowers the β-lactam MIC from 512 to 8 µg/mL against S. aureus USA300. MAC545496 also synergizes with Cefuroxime and Oxacillin against a collection of ten S. aureus clinical isolates. In addition, MAC-545496 potentiates the effect of Cefuroxime against representatives of other circulating MRSA strains such as USA100, USA400 and USA500 to different extents, with the exception of CMRSA4, a USA200/EMRSA16 isolate. MAC-545496 also synergizes with the antimicrobial peptides colistin and polymyxin B[1]. MAC-545496 shows inhibition of mprF expression in a concentration-dependent manner; the IC50 value is 0.0376 µg/mL[1]. MAC-545496 also inhibits the citrateinduced biofilm formation in the wild type in a concentration dependent manner[1].

In vivo, MAC-545496 is effective as a monotherapy for MRSA infected Galleria mellonella larvae. MAC-545496 activity is evidenced by increased survival of the drug-treated larvae as compared to infected untreated ones. This corresponded to concentration-dependent killing of S. aureus in the hemolymph of the larvae observed from the CFUs recovered from the hemolymph 200 min after infection. Treatment of S. aureus-infected larvae with MAC-545496 occurred 30min after infection that mimics acquiring bacterial infection before initiating antimicrobial therapy [1].

[1]. El-Halfawy OM, et al. Discovery of an antivirulence compound that reverses β-lactam resistance in MRSA. Nat Chem Biol. 2019 Nov 25.