Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis

Kevin Pethe, Pablo Bifani, Jichan Jang, Sunhee Kang, Seijin Park, Sujin Ahn, Jan Jiricek, Juyoung Jung, Hee Kyoung Jeon, Jonathan Cechetto, Thierry Christophe, Honggun Lee, Marie Kempf, Mary Jackson, Anne J. Lenaerts, Ha Pham, Victoria Jones, Min Jung Seo, Young Mi Kim, Mooyoung SeoJeong Jea Seo, Dongsik Park, Yoonae Ko, Inhee Choi, Ryangyeo Kim, Se Yeon Kim, Seungbin Lim, Seung Ae Yim, Jiyoun Nam, Hwankyu Kang, Haejin Kwon, Chun Taek Oh, Yoojin Cho, Yunhee Jang, Junghwan Kim, Adeline Chua, Bee Huat Tan, Mahesh B. Nanjundappa, Srinivasa P.S. Rao, Whitney S. Barnes, René Wintjens, John R. Walker, Sylvie Alonso, Saeyeon Lee, Jungjun Kim, Soohyun Oh, Taegwon Oh, Ulf Nehrbass, Sung Jun Han, Zaesung No, Jinhwa Lee, Priscille Brodin, Sang Nae Cho, Kiyean Nam, Jaeseung Kim

Research output: Contribution to journalArticle

290 Citations (Scopus)

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 tuberculosis3-5, several of which are currently in clinical trials6-8. 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.

Original languageEnglish
Pages (from-to)1157-1160
Number of pages4
JournalNature Medicine
Volume19
Issue number9
DOIs
Publication statusPublished - 2013 Sep

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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    Pethe, K., Bifani, P., Jang, J., Kang, S., Park, S., Ahn, S., Jiricek, J., Jung, J., Jeon, H. K., Cechetto, J., Christophe, T., Lee, H., Kempf, M., Jackson, M., Lenaerts, A. J., Pham, H., Jones, V., Seo, M. J., Kim, Y. M., ... Kim, J. (2013). Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis. Nature Medicine, 19(9), 1157-1160. https://doi.org/10.1038/nm.3262