Potency boost of a Mycobacterium tuberculosis dihydrofolate reductase inhibitor by multienzyme F₄₂₀H₂-dependent reduction.

ABSTRACT: Triaza-coumarin (TA-C) is a Mycobacterium tuberculosis (Mtb) dihydrofolate reductase (DHFR) inhibitor with an IC₅₀ (half maximal inhibitory concentration) of ∼1 µM against the enzyme. Despite this moderate target inhibition, TA-C shows exquisite antimycobacterial activity (MIC₅₀, concentration inhibiting growth by 50% = 10 to 20 nM). Here, we investigated the mechanism underlying this potency disconnect. To confirm that TA-C targets DHFR and investigate its unusual potency pattern, we focused on resistance mechanisms. In Mtb, resistance to DHFR inhibitors is frequently associated with mutations in thymidylate synthase thyA, which sensitizes Mtb to DHFR inhibition, rather than in DHFR itself. We observed thyA mutations, consistent with TA-C interfe

SUBMITTER: Aragaw WW 

PROVIDER: S-EPMC8237569 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature