Development of nitroreductase-activated inhibitors to treat mycobacterial infections

Tarn Biosciences, Inc. (Tarn) is discovering and bringing to market novel drugs for the treatment of mycobacterial infections, including both drug-susceptible and drug-resistant (DR) tuberculosis (TB) and non- tuberculous mycobacterial (NTM) infections. TB is caused by the bacterium Mycobacterium tuberculosis (Mtb) and NTM infections are caused by diverse mycobacterial species, including M. abscessus (Mab). TB is the greatest bacterial killer in the world while NTM is a serious and growing problem worldwide, including in developed nations. Both TB and NTM are primarily pulmonary infections that cause chronic, debilitating, and deadly disease. The goal of this STTR is to develop the novel nitroreductase-dependent inhibitors, the parent compound HC2210, as new treatments for TB and NTM infections. With the recent approval of pretomanid and delamanid for TB treatment, nitroreductase-dependent compounds have emerged as important agents to control TB. Pretomanid and delamanid kill Mtb by targeting essential cellular processes , including respiration or cell wall biogenesis, and are effective against nonreplicating Mtb. Notably, pretomanid and delamanid are not active against Mab and the pharmacokinetics (PK) profile and side effects of the compounds reduce their clinical utility for certain TB patients. Due to these challenges, there is an unmet need to develop new antimycobacterial nitroreductase-dependent compounds with improved therapeutic utility and activity against NTMs. We discovered a new series of nitrofurans, represented by HC2210, that are potent inhibitors of both Mtb and Mab. HC2210 is >20-fold more potent than pretomanid, with a 30 nM half-maximal effective concentration against Mtb. When HC2210 was administered orally in a chronic murine model of TB infection, it reduced Mtb burden by >10-fold in the lungs and spleens of infected mice. These proof-of-concept data show HC2210 is orally bioavailable, tolerable and efficacious in a chronic mouse model of Mtb infection, reaching a critical milestone in the development of a new antimicrobial. The product of this proposal is H2210 analogs. HC2210 has favorable drug-like properties, and is potent and orally efficacious in animal models. Michigan State University holds patent applications for the use of HC2210 to treat TB and NTM infection and composition of chemical matter for HC2210 and related analogs. MSU is in licensing negotiations with Tarn Biosciences to purse further development of the series. The goal of this Phase I project is to optimize and prioritize three HC2210 analogs with favorable in vitro and in vivo drug- like properties and demonstrate efficacy in chronic murine models of Mtb and Mab infection.