Optimization of antitubercular compounds against a novel mycobacterium tuberculosis target, aspc - tuberculosis (TB) is once again the leading cause of death from infectious disease

The National Institute of Allergy and Infectious Diseases awarded Trudeau Institute Inc. $921,320 on January 28, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to optimize antitubercular compounds targeting a novel Mycobacterium tuberculosis enzyme.

Trudeau will advance the lead compound TI-374, originally developed to treat cognitive impairment in schizophrenia and psychiatric disorders, toward clinical viability as a tuberculosis therapeutic. TI-374 demonstrates high potency (0.1 mg/mL) against M. tuberculosis and acts on alanine aminotransferase (ASPC), a novel TB target identified as essential in transposon mutagenesis screening and validated as important for bacterial survival in murine infection models. The compound possesses drug-like and lead-like properties and a distinctive chemical structure that addresses major obstacles in antibiotic development. Work will employ ligand-based approaches to expand structure-activity relationships, optimize potency for efficacy against MTB ASPC using antibiotic susceptibility assays, and conduct on-target ASPC enzyme validation. Place of performance is Saranac Lake, New York. The award runs through December 31, 2030.

Current TB treatments are complex, lengthy and have undesirable side effects. As a result, cases of multi-drug resistant and extensively-drug resistant TB are on the rise. Compounding this problem of rising drug resistance is the notable lack of innovation in drug discovery; new antibiotics are often chemically similar, target the same few bacterial pathways (e.g. cell wall, nucleic acid and protein synthesis) for which mechanisms of resistance are well established, and are slow to come to market. Therefore, the discovery of chemically distinct therapeutics that act via novel mechanisms is necessary to overcome the emergence of resistant strains. In addition, drug repurposing represents an attractive option to mitigate cost, time and safety risk associated with antibiotic development. We have identified a molecule (TI-374) with high potency (0.1 ΜG/ML) against mycobacterium tuberculosis (MTB), originally identified to treat cognitive impairment associated with schizophrenia and psychiatric disorders. Preliminary data indicates that this molecule acts on a novel MTB target, the alanine aminotransferase aspc, which was observed to be essential in a transposon mutagenesis screen and we show to be important for bacterial survival in a murine model of MTB infection. TI-374 has drug-like and lead- like properties, a novel mechanism of action and a distinctive chemical structure, thereby addressing the major hurdles plaguing antibiotic drug development. We have proposed to optimize TI-374 against MTB and progress IT into a lead compound. Key ideas underlying our approach are as follows: (i) taking a ligand-based approach, we will expand structure-activity relationship (SAR) and optimize potency for efficacy against MTB aspc using antibiotic susceptibility assays as well as on-target aspc enzymatic assays and off-target enzymatic assays to counter screen against the original human target and a known human ortholog, (II) advancement of potent, on- target analogs to extensive in vitro adme and in vivo PK studies and (III) characterization of pharmacological and genetic inhibition of aspc in a murine chronic infection model. With completion of this proposal, we expect to identify 1-2 advanced leads, as well as validate aspc as a novel druggable target, enabling further studies for the treatment of MTB. We believe the proposal provides an innovative approach to develop new therapeutic avenues to treat MTB infections, which is an urgent unmet need.