MAC-545496, a GraR Inhibitor, Reverses β-lactam Resistance in MRSA

Staphylococcus aureus is a major bacterial human pathogen that causes a wide variety of clinical manifestations. Staphylococcus aureus is the leading cause of infections worldwide, and methicillin-resistant strains (MRSA) are emerging. Infections are common both in community-acquired as well as hospital-acquired settings and treatment remains challenging to manage due to the emergence of multi-drug resistant strains such as MRSA (Methicillin-Resistant Staphylococcus aureus). Staphylococcus aureus does not normally cause infection on healthy skin; however, S. aureus enters the bloodstream or internal tissues, these bacteria may cause a variety of potentially serious infections. MAC-545496 is a nanomolar inhibitor of GraR.

In this study, using a cell-based screen of 45,000 diverse synthetic compounds, researchers discovered a potent bioactive compound MAC-545496. GraR (glycopeptide-resistance-associated protein R) is a response regulator protein of a multicomponent regulatory system. Moreover, GraR is an important virulence factor and determinant of antibiotic resistance. Furthermore, GraR and its regulatory system are important for virulence of S. aureus. Unlike conventional antibiotics, MAC-545496 neither kills the staph infection nor halts its growth on its own. MAC-545496 cripples MRSA’s ability to cause infection by diminishing its tolerance to the hostile components of the immune system and blocking the bacterium’s capacity to resist the action of several front-line antibiotics.

MAC-545496 reverses β-lactam resistance in the community-acquired MRSA USA300 strain. Especially, MAC-545496 serves as an antivirulence agent alone. MAC-545496 attenuates MRSA virulence in Galleria mellonella larvae. Besides, MAC-545496 inhibits biofilm formation and abrogates intracellular survival in macrophages. Particularly, MAC-545496 has value as an antibacterial lead series of a mechanism to combat drug-resistant Staphylococcal infections.

All in all, MAC-545496 is an antivirulence compound that reverses β-lactam resistance in methicillin-resistant strains (MRSA).

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