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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References
Zhao, Y. et al. National survey of drug-resistant tuberculosis in China. N. Engl. J. Med. 366, 2161â2170 (2012).
Chaisson, R.E. & Nuermberger, E.L. Confronting multidrug-resistant tuberculosis. N. Engl. J. Med. 366, 2223â2224 (2012).
Stover, C.K. et al. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature 405, 962â966 (2000).
Andries, K. et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis. Science 307, 223â227 (2005).
Makarov, V. et al. Benzothiazinones kill Mycobacterium tuberculosis by blocking arabinan synthesis. Science 324, 801â804 (2009).
Diacon, A.H. et al. Early bactericidal activity and pharmacokinetics of PA-824 in smear-positive tuberculosis patients. Antimicrob. Agents Chemother. 54, 3402â3407 (2010).
Diacon, A.H. et al. Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrug-resistant tuberculosis: long-term outcome, tolerability, and effect on emergence of drug resistance. Antimicrob. Agents Chemother. 56, 3271â3276 (2012).
Gler, M.T. et al. Delamanid for multidrug-resistant pulmonary tuberculosis. N. Engl. J. Med. 366, 2151â2160 (2012).
Christophe, T. et al. High content screening identifies decaprenyl-phosphoribose 2â² epimerase as a target for intracellular antimycobacterial inhibitors. PLoS Pathog. 5, e1000645 (2009).
Pethe, K. et al. A chemical genetic screen in Mycobacterium tuberculosis identifies carbon-source-dependent growth inhibitors devoid of in vivo efficacy. Nat. Commun. 1, 57 (2010).
Stanley, S.A. et al. Identification of novel inhibitors of M. tuberculosis growth using whole cell based high-throughput screening. ACS Chem. Biol. 7, 1377â1384 (2012).
Adams, K.N. et al. Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism. Cell 145, 39â53 (2011).
No, Z. et al. Anti-infective compounds. International patent application WO 2011113606 A1 (2011).
Katritzky, A.R., Xu, Y.J. & Tu, H. Regiospecific synthesis of 3-substituted imidazo[1,2-a]pyridines, imidazo[1,2-a]pyrimidines, and imidazo[1,2-c]pyrimidine. J. Org. Chem. 68, 4935â4937 (2003).
Koul, A., Arnoult, E., Lounis, N., Guillemont, J. & Andries, K. The challenge of new drug discovery for tuberculosis. Nature 469, 483â490 (2011).
Rullas, J. et al. Fast standardized therapeutic-efficacy assay for drug discovery against tuberculosis. Antimicrob. Agents Chemother. 54, 2262â2264 (2010).
Shang, S. et al. Activities of TMC207, rifampin, and pyrazinamide against Mycobacterium tuberculosis infection in guinea pigs. Antimicrob. Agents Chemother. 55, 124â131 (2011).
Abrahams, K.A. et al. Identification of novel imidazo[1,2-a]pyridine inhibitors targeting M. tuberculosis QcrB. PLoS ONE 7, e52951 (2012).
Matsoso, L.G. et al. Function of the cytochrome bc1-aa3 branch of the respiratory network in mycobacteria and network adaptation occurring in response to its disruption. J. Bacteriol. 187, 6300â6308 (2005).
Sassetti, C.M., Boyd, D.H. & Rubin, E.J. Genes required for mycobacterial growth defined by high density mutagenesis. Mol. Microbiol. 48, 77â84 (2003).
Moraski, G.C. et al. Advent of imidazo[1,2-a]pyridine-3-carboxamides with potent multi- and extended drug resistant antituberculosis activity. ACS Med. Chem. Lett. 2, 466â470 (2011).
Mak, P.A. et al. A high-throughput screen to identify inhibitors of ATP homeostasis in non-replicating Mycobacterium tuberculosis. ACS Chem. Biol. 7, 1190â1197 (2012).
Fry, M. & Pudney, M. Site of action of the antimalarial hydroxynaphthoquinone, 2-[trans-4-(4â²-chlorophenyl) cyclohexyl]-3-hydroxy-1,4-naphthoquinone (566C80). Biochem. Pharmacol. 43, 1545â1553 (1992).
von Jagow, G. & Link, T.A. Use of specific inhibitors on the mitochondrial bc1 complex. Methods Enzymol. 126, 253â271 (1986).
Kleinschroth, T. et al. X-ray structure of the dimeric cytochrome bc1 complex from the soil bacterium Paracoccus denitrificans at 2.7-Ã resolution. Biochim. Biophys. Acta 1807, 1606â1615 (2011).
Esser, L. et al. Inhibitor-complexed structures of the cytochrome bc1 from the photosynthetic bacterium Rhodobacter sphaeroides. J. Biol. Chem. 283, 2846â2857 (2008).
Hunte, C., Koepke, J., Lange, C., Rossmanith, T. & Michel, H. Structure at 2.3 Ã resolution of the cytochrome bc1complex from the yeast Saccharomyces cerevisiae co-crystallized with an antibody Fv fragment. Structure 8, 669â684 (2000).
Esser, L. et al. Crystallographic studies of quinol oxidation site inhibitors: a modified classification of inhibitors for the cytochrome bc1 complex. J. Mol. Biol. 341, 281â302 (2004).
Lin, P.L. et al. Metronidazole prevents reactivation of latent Mycobacterium tuberculosis infection in macaques. Proc. Natl. Acad. Sci. USA 109, 14188â14193 (2012).
Christophe, T., Ewann, F., Jeon, H.K., Cechetto, J. & Brodin, P. High-content imaging of Mycobacterium tuberculosisâinfected macrophages: an in vitro model for tuberculosis drug discovery. Future Med. Chem. 2, 1283â1293 (2010).
Martin, A. et al. Multicenter study of MTT and resazurin assays for testing susceptibility to first-line anti-tuberculosis drugs. Int. J. Tuberc. Lung Dis. 9, 901â906 (2005).
Kurabachew, M. et al. Lipiarmycin targets RNA polymerase and has good activity against multidrug-resistant strains of Mycobacterium tuberculosis. J. Antimicrob. Chemother. 62, 713â719 (2008).
Carmichael, J., DeGraff, W.G., Gazdar, A.F., Minna, J.D. & Mitchell, J.B. Evaluation of a tetrazolium-based semiautomated colorimetric assay: assessment of chemosensitivity testing. Cancer Res. 47, 936â942 (1987).
Rao, S.P., Alonso, S., Rand, L., Dick, T. & Pethe, K. The protonmotive force is required for maintaining ATP homeostasis and viability of hypoxic, nonreplicating Mycobacterium tuberculosis. Proc. Natl. Acad. Sci. USA 105, 11945â11950 (2008).
Koul, A. et al. Diarylquinolines are bactericidal for dormant mycobacteria as a result of disturbed ATP homeostasis. J. Biol. Chem. 283, 25273â25280 (2008).
Crespi, C.L., Miller, V.P. & Penman, B.W. Microtiter plate assays for inhibition of human, drug-metabolizing cytochromes P450. Anal. Biochem. 248, 188â190 (1997).
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, 1157â1160 (2013). https://doi.org/10.1038/nm.3262
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DOI: https://doi.org/10.1038/nm.3262
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