pbtz169

Description: PBTZ169 (also known as Macozinone, an 8-Nitro-benzothiazinones (BTZs) analog) is a novel inhibitor of decaprenyl-phosphoribose-epimerase (DprE1) that displays nanomolar bactericidal activity against Mycobacterium tuberculosis in vitro. DprE1 is an essential enzyme involved in the cell wall biosynthesis of Corynebacterineae. Structure-activity relationship (SAR) studies revealed the 8-nitro group of the BTZ scaffold to be crucial for the mechanism of action, which involves formation of a semimercaptal bond with Cys387 in the active site of DprE1. When tested against thirty Nocardia brasiliensis isolates, the MIC50 and MIC90 values for PBTZ169 were 0.0075 and 0.03 ug/mL, respectively. Because Nocardia is a potential intracellular bacterium, a THP-1 macrophage monolayer was infected with N. brasiliensis HUJEG-1 and then treated with PBTZ169, resulting in a decrease in the number of colony-forming units (CFUs) at a concentration of 0.25X the in vitro value. The in vivo activity was evaluated after infecting female BALB/c mice in the right hind food-pad. After 6 weeks, treatment was initiated with PBTZ169 and its activity was compared with the first generation compound, BTZ043. Both BTZ compounds were administered at 100 mg/kg twice daily by gavage, and sulfamethoxazole/trimethoprim (SXT), at 100 mg/kg sulfamethoxazole, was used as a positive control. After 22 weeks of therapy, only PBTZ169 and SXT displayed statistically significant activity.

References: Antimicrob Agents Chemother. 2015 Aug; 59(8):4446-52; PLoS Negl Trop Dis. 2015 Oct 16; 9(10):e0004022.