TCA1 is a small molecule with activity against drug-susceptible and -resistant Mycobacterium tuberculosis (Mtb). TCA1 inhibits enzymes involved in cell wall and molybdenum cofactor biosynthesis, such as DprE1 and MoeW.In Vitro: TCA1 shows bactericidal activity against both replicating (WT and drug resistant) and nonreplicating Mycobacterium tuberculosis (Mtb). TCA1 inhibits biofilm formation by Mtb H37Rv.
TCA1 shows selective inhibitory activity against bacterial growth-it is inactive against Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa, suggesting that the target for its bactericidal activity is specific to the genus Mycobacterium.In Vivo: TCA1 (40 mg/kg; oral gavage; 1 time/d for 5 d/week; for 4 weeks) is efficacious in acute and chronic Mtb infection mouse models.
In a mouse model of Mtb infection, after i.v. administration, TCA1 exhibits a low clearance and steady-state volume of distribution, with an elimination half-life of 0.73 h. After oral administration of 20 and 50 mg/kg in solution formulation, TCA1 shows a high Cmax (2122 and 5653 nM, respectively), moderate exposure with oral bioavailability ranging from 19% to 46%, and a half-life of 1.8 h.BALB/c mice infected with Mtb H37Rv40 mg/kgOral gavage; 1 time/d for 5 d/week; for 4 weeksEffectively inhibits Mtb in vivo.