Development of GuaB Inhibitors to Treat Mycobacterium tuberculosis Infection.

Abstract:

Mycobacterium tuberculosis (Mtb) is responsible for more deaths per year than any other infectious disease. Resistance of circulating Mtb to the standard of care treatment regimen is an urgent global health crisis for which novel antibiotic treatments are needed. We have developed extremely potent, orally bioavailable, small-molecule inhibitors of inosine 5′-monophosphate dehydrogenase (GuaB) that catalyze the rate-limiting step in de novo guanine biosynthesis. The inhibitors exhibited bactericidal activity against Mtb in extracellular, intracellular, and hypoxic environments that capture features of advanced disease pathology in patients. Mtb GuaB2 inhibitors (GuaBi) were efficacious in three different in vivo mouse models of Mtb lung infection: the C57BL/6 super acute, C57BL/6 chronic, and C3HeB/FeJ (Kramnik) models. In the chronic BALB/c infection model of primarily intracellular Mtb, no benefit was observed, whereas in the C3HeB/FeJ model, a bedaquiline, pretomanid, and moxifloxacin treatment regimen that included GuaBi led to a rapid elimination of culturable Mtb infection in half of the mice. Notably, the C3HeB/FeJ model recapitulates advanced pathophysiology and heterogeneous disease that includes caseous necrotic granulomas, intracellular and extracellular reservoirs of Mtb, and lethal progressive infection. These results support further evaluation of a GuaBi-containing therapeutic regimen in relapse-capable preclinical models.