Advancements in Tuberculosis and Lung Diseases

Biography

Biography: Pooja Hegde

Abstract

Tuberculosis (TB) is the world’s most deadly infectious disease resulting in nearly 1.5 million deaths annually and infecting nearly one-quarter of the population. para-Aminosalicylic acid (PAS), an important second-line agent for treating drug-resistant mycobacteria, has low bioavailability and rapid clearance that necessitate high daily doses of up to 12 grams/day, which in turn causes severe gastrointestinal disturbances by disruption of gut microbiota and host epithelial cells.  We have developed a series of prodrugs to increase the oral bioavailability that lowers intestinal exposure and prevents undesirable bioactivation by the gut microbiome to non-natural, cytotoxic folate species. The conceptually simple prodrug approach does not address the intrinsic rapid clearance of PAS by N-acetyltransferase (NAT), thus we have also prepared analogs to lower clearance of PAS enzymes by attenuating N-acetylation through steric and electronic deactivation of the para-amino group. Combination of these dual approaches is expected to afford a next-generation PAS analog with improved drug disposition properties to prevent adverse reactions as well as the development of resistance.