Structural and mechanistic study of a novel inhibitor of M. tuberculosis cytochrome bc1:aa3
Abstract
Abstract Drug-resistant tuberculosis (TB) continues to challenge treatment options, necessitating the exploration of new compounds of novel targets. The mycobacterial respiratory complex cytochrome bc1:aa3 has emerged as a promising target, exemplified by the success of first-in-class inhibitor Q203 in phase 2 clinical trial. However, to fully exploit the potential of this target and to identify the best-in-class inhibitor more compounds need evaluation. Here, we introduce JNJ-2901, a novel inhibitor of the M. tuberculosis cytochrome bc1:aa3, demonstrating activity against multidrug-resistant M. tuberculosis clinical strains at sub-nanomolar concentration and 4-log reduction in bacterial burden in mouse model of TB infection. Inhibitory studies on purified enzyme validate the nanomolar inhibitions observed in mycobacterial cells. Additionally, cryo-EM structure analysis of cytochrome bc1:aa3 bound to JNJ-2901 reveals the binding pocket at the menaquinol oxidation site (Qp), akin to other substate analogue inhibitors like Q203 and TB47. Validation of binding site is further achieved by generating and isolating the JNJ-2901 resistant mutations in M. tuberculosis, followed by purification and resistance analysis of the resistant cytochrome bc1:aa3 complex. Our comprehensive work lay the foundation for further clinical validations of JNJ-2901.
Read the paper
Related studies
- Synthesis, In Vitro and In Silico Molecular Docking Studies of Novel Phthalimide–Pyrimidine Hybrid Analogues to Thalidomide as Potent Antitubercular Agents
- Exploring the inhibitory performance of expired moxifloxacin and norfloxacin on copper corrosion in saline environment
- Molecular investigation of antimicrobial peptides against Helicobacter pylori proteins using a peptide-protein docking approach
- Screening of novel narrow-spectrum benzofuroxan derivatives for the treatment of multidrug-resistant tuberculosis through in silico, in vitro, and in vivo approaches
- Synthesis, Characterization, Anticancer, Antioxidant, and In Silico Evaluation of Semicarbazides and Thiosemicarbazides
- Fast and accurate prediction of drug induced proarrhythmic risk with sex specific cardiac emulators
Go deeper in Evidence Hub
Evidence Hub adds a study data sheet (design, sample size, evidence level, key numbers), an AI summary and a chat grounded in the paper's text.