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.
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Acknowledgements
This work was supported by a National Research Foundation of Korea grant funded by the Korean government Ministry of Education, Science and Technology (2012-00011), the Korea Institute of Science and Technology Information, Gyeonggi-do and Institut National de la Santé et de la Recherche Médicale-Avenir. R.W. received support from the Belgian Fund for Scientific Research. We thank T. Diagana and P. Smith for critical reading of the manuscript.
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Jaeseung Kim, K.N. and K.P. supervised the project, H.K.J., J.C., P. Brodin, T.C., H.L., K.P., R.K., S.-A.Y., U.N. and J. Jang designed and performed the chemical genetics screen and growth inhibition experiments, S. Kang, M.J.S., S. Lee, Y.M.K., M.S., J.J.S., D.P., Y.K., I.C., Jaeseung Kim, Z.N., J.L. and J. Jiricek designed and synthesized the compounds, J. Jang, K.P. and S.Y.K. designed and performed the ATP quantification experiments, K.P., J. Jang, S. Alonso, C.-T.O., Y.C., Y.J., Junghwan Kim, S.-J.H., M.J., H.P., P. Bifani and V.J. designed and performed the mode of action studies, S.P., S. Ahn, H. Kang, H. Kwon, J.N., S. Lim, K.N. and A.J.L. performed and designed in vivo pharmacokinetic and efficacy experiments, J. Jung and A.J.L. performed and interpreted the histopathology experiments, S. Ahn, K.N., S.O. and Jungjun Kim designed or managed the in vitro toxicology assessment and the in vitro pharmacokinetic profiling, J.R.W. and W.S.B. designed and performed the whole-genome sequencing experiments, T.O. and S.-N.C. tested Q203 against MDR and XDR clinical isolates and other mycobacteria, Y.K., I.C. and R.W. performed bioinformatics analysis, P. Bifani, A.C., B.H.T., M.B.N., S.P.S.R., K.P. and S.-A.Y. designed and performed experiments for target validation, M.K. tested Q203 against a panel of microorganisms, K.P. wrote the manuscript with contributions from other authors.
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K.N., Jungjun Kim, S.O. and S.L. are employees of Qurient, which has been developing Q203 as a therapeutic agent against MDR and XDR tuberculosis. Jaeseung Kim, S.-J.H., J.L., S.L., U.N. and P. Bordin have shares in Qurient.
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Pethe, K., Bifani, P., Jang, J. et al. Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis. Nat Med 19, 1157–1160 (2013). https://doi.org/10.1038/nm.3262
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DOI: https://doi.org/10.1038/nm.3262
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