Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis
Top Cited Papers
- 4 August 2013
- journal article
- letter
- Published by Springer Science and Business Media LLC in Nature Medicine
- Vol. 19 (9), 1157-1160
- https://doi.org/10.1038/nm.3262
Abstract
New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide1,2. The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis3,4,5, several of which are currently in clinical trials6,7,8. However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis.Keywords
This publication has 35 references indexed in Scilit:
- Metronidazole prevents reactivation of latent Mycobacterium tuberculosis infection in macaquesProceedings of the National Academy of Sciences of the United States of America, 2012
- Confronting Multidrug-Resistant TuberculosisNew England Journal of Medicine, 2012
- Randomized Pilot Trial of Eight Weeks of Bedaquiline (TMC207) Treatment for Multidrug-Resistant Tuberculosis: Long-Term Outcome, Tolerability, and Effect on Emergence of Drug ResistanceAntimicrobial Agents and Chemotherapy, 2012
- Advent of Imidazo[1,2-a]pyridine-3-carboxamides with Potent Multi- and Extended Drug Resistant Antituberculosis ActivityACS Medicinal Chemistry Letters, 2011
- A chemical genetic screen in Mycobacterium tuberculosis identifies carbon-source-dependent growth inhibitors devoid of in vivo efficacyNature Communications, 2010
- Fast Standardized Therapeutic-Efficacy Assay for Drug Discovery against TuberculosisAntimicrobial Agents and Chemotherapy, 2010
- Inhibitor-complexed Structures of the Cytochrome bc1 from the Photosynthetic Bacterium Rhodobacter sphaeroidesJournal of Biological Chemistry, 2008
- Function of the Cytochrome bc 1 - aa 3 Branch of the Respiratory Network in Mycobacteria and Network Adaptation Occurring in Response to Its DisruptionJournal of Bacteriology, 2005
- Regiospecific Synthesis of 3-Substituted Imidazo[1,2-a]pyridines, Imidazo[1,2-a]pyrimidines, and Imidazo[1,2-c]pyrimidineThe Journal of Organic Chemistry, 2003
- Microtiter Plate Assays for Inhibition of Human, Drug-Metabolizing Cytochromes P450Analytical Biochemistry, 1997