Matheus Andrade Meirelles, Vitor M. Almeida, Jaryd R. Sullivan, Ian de Toledo, Caio Vinicius dos Reis, Micael Rodrigues Cunha, Rachel Zigweid, Abraham Shim, Banumathi Sankaran, Elijah L. Woodward, Steve Seibold, Lijun Liu, Mohammad Rasel Mian, Kevin P. Battaile, Jennifer Riley, Christina Duncan, Frederick R. C. Simeons, Liam Ferguson, Halimatu Joji, Kevin D. Read, Scott Lovell, Bart L. Staker, Marcel A. Behr, Ronaldo A. Pilli, Rafael M. Couñago.
J. Med. Chem. 2024, 67, 21, 19143–19164
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 underscores the potential of compound 8 as a promising candidate for the in vivo validation of DHFR as an effective treatment against NTM infections.