Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active against <i>Mycobacterium abscessus</i> and <i>Mycobacterium avium</i>, Two Emerging Human Pathogens.

ABSTRACT: Nontuberculous mycobacteria (NTM) are emerging human pathogens linked to severe pulmonary diseases. Current treatments involve the prolonged use of multiple drugs and are often ineffective. Bacterial dihydrofolate reductase (DHFR) is a key enzyme targeted by antibiotics in Gram-negative bacterial infections. However, existing DHFR inhibitors designed for Gram-negative bacteria often fail against mycobacterial DHFRs. Here, we detail the rational design of NTM DHFR inhibitors based on P218, a malarial DHFR inhibitor. We identified compound 8, a 2,4-diaminopyrimidine exhibiting improved pharmacological properties and activity against purified DHFR, and whole cell cultures of two predominant NTM species: Mycobacterium avium and Mycobacterium abscessus. This study un

SUBMITTER: Andrade Meirelles M 

PROVIDER: S-EPMC12286596 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature