RT Journal Article
SR Electronic
T1 Mechanism of selectivity reveals novel antifolate drug interactions
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.09.18.304022
DO 10.1101/2020.09.18.304022
A1 Shannon Lynn Kordus
A1 Elise A. Lamont
A1 Michael D. Howe
A1 Allison A. Bauman
A1 William McCue
A1 Barry Finzel
A1 Anthony D. Baughn
YR 2020
UL http://biorxiv.org/content/early/2020/09/19/2020.09.18.304022.abstract
AB 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.Competing Interest StatementThe authors have declared no competing interest.