Mechanism of selectivity reveals novel antifolate drug interactions

Abstract

Antimicrobial agents that target a specific pathogen of interest is the gold standard in drug design. para-Aminosalicylic acid (PAS), remains a cornerstone therapy, in the treatment against Mycobacterium tuberculosis, owing to its high level of selectivity. Despite its high level of selectivity, PAS has been reassigned to treat drug-resistant strains of M. tuberculosis because it causes severe gastrointestinal (GI) distress that results in poor patient compliance. We have previously shown PAS inhibits the folate biosynthetic pathway specifically inhibiting dihydrofolate reductase1,2. In this study, we sought to determine the mechanistic basis of PAS selectivity and determined that PAS can be utilized in folate biosynthesis by other bacterial pathogens. The utilization of PAS ultimately led to the antagonism of key antibiotics, specifically the sulfonamides, used to prophylactically treat individuals with HIV-AIDS3. In addition, we found many bacteria in the GI tract could also utilize PAS to make a hydroxy-folate species which resulted in GI toxicity. Using sulfonamides as a tool to prevent PAS associated toxicity in the GI tract, we discovered that the sulfonamides antagonized the antimycobacterial activity of PAS. These findings indicate a new need for understanding the mechanisms of selective therapies and more important, that HIV-AIDS/M. tuberculosis co-infected individuals should avoid co-treatment of PAS and sulfonamides.

Hybridization Approach Toward Novel Antituberculars: Design, Synthesis, and Biological Evaluation of Compounds Combining Pyrazinamide and 4-Aminosalicylic Acid

“…One last remark, PAS exerts antimicrobial activity characteristically against Mtb strains and not any other bacteria as the latter can utilize PAS as a surrogate of PABA in the folate biosynthesis pathway. This fact explains the in vitro activity of title compounds against Mtb but not against other bacteria and in return strengthens the argument that DHFR is their molecular target …”

“…This fact explains the in vitro activity of title compounds against Mtb but not against other bacteria and in return strengthens the argument that DHFR is their molecular target. 23 In Silico Binding to Mycobacterial DHFR Our biochemical studies indicated that compound 11 inhibits the DHFR activity in Mtb H37Ra on the whole-cell level. To assess the possible binding of 11 to mycobacterial DHFR, we performed molecular docking to pdb id: 5u26, representing the most common conformation of Mtb DHFR in the PDB database.…”