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. In this project we aim to improve the bioavailability of PAS, while retaining its anti-mycobacterial activity. We have developed a series of prodrugs that substantially increase the oral bioavailability, which prevents intestinal accumulation as well as undesirable bioactivation by the gut microbiome to non-natural folate species that exhibit cytotoxicity. The conceptually simple prodrug approach does not address the intrinsic rapid clearance of PAS by N-acetyltransferase (NAT), thus we have also designed bioisosteric replacements to the PAS scaffold to lower clearance of PAS enzymes by sterically blocking N-acetylation and electronic deactivation of the para-amino group. By the combination of these dual approaches together we hypothesize to provide a next-generation PAS drug that can potentially be given at substantially lower doses to prevent adverse reactions and help prevent development of resistance through achieving higher serum concentrations.

Design and evaluation of orally active prodrugs and analogues of PAS

ACS Spring Meeting 2021

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