Tuberculosis (TB), an infectious disease caused by the pathogen <i>Mycobacterium tuberculosis </i>(Mtb), is a major cause of suffering worldwide. Pyrazinamide (PZA), a critical component of the first-line TB treatment regimen, is primarily responsible for sterilization <i>in vivo</i> and shortens the TB therapy by 3 months. PZA is converted by pyrazinamidase, within the bacteria, to the active moiety, pyrazinoic acid (POA). Pyrazinamidase mutations are a major cause of PZA resistance. POA induces targeted protein degradation of the enzyme PanD, a crucial component of the coenzyme A biosynthetic pathway essential for M. tuberculosis survival under both replicating and non-replicating conditions. Based on the mechanism of action of POA, using structure-based drug design, we designed several POA analogs. We prepared and tested ring isosteres, carboxylic acid bioisosteres as well as ring substitutions to study the structure activity relationships of the POA scaffold. All the analogs were evaluated for their anti-tubercular activity and a few representative molecules were evaluated for their binding affinity, towards PanD, through isothermal titration calorimetry. We report that analogs with ring and carboxylic acid bioisosteres did not significantly enhance the microbial potency, whereas the ring substituted analogs showed some promise. The 3 and 5 position alkylamino-POA analogs were found to be 5 to 10–fold more potent anti-TB agents as compared to POA. The active compounds bound to PanD with varied affinities. Further development and mechanistic analysis of these analogs may result in alternatives that can overcome PZA resistance.

Structure activity relationship of pyrazinoic acid analogs as potential antimycobacterial agents

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.