Journal ArticleDOI
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,Ju-Young Jung,Hee Kyoung Jeon,Jonathan Cechetto,Thierry Christophe,Honggun Lee,Marie Kempf,Mary Jackson,Anne J. Lenaerts,Hang Ohuong Pham,Victoria Jones,Min Jung Seo,Young-Mi Kim,Mooyoung Seo,Jeong 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 C. Y. Chua,Bee Huat Tan,Mahesh Nanjundappa,Srinivasa P. S. Rao,Whitney 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 +54 more
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TLDR
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.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 worldwide. 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 tuberculosis, several of which are currently in clinical trials. 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.read more
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Journal ArticleDOI
Strategies to Combat Multi-Drug Resistance in Tuberculosis.
TL;DR: The research aimed at identifying novel small molecule leads and associated targets against TB toward contributing to the global TB drug discovery and development pipeline and screening of various small molecule chemical libraries in phenotypic whole-cell based assays is highlighted.
Journal ArticleDOI
The anti-mycobacterial activity of the cytochrome bcc inhibitor Q203 can be enhanced by small-molecule inhibition of cytochrome bd.
Ping Lu,Amer H. Asseri,Amer H. Asseri,Martijn Kremer,J.J. Maaskant,Roy Ummels,Holger Lill,Dirk Bald +7 more
TL;DR: It is shown that inhibition of cytochrome bd, a parallel branch of the mycobacterial respiratory chain, by aurachin D invoked bactericidal activity of Q203, indicating that simultaneously targeting the cy tochrome bcc complex of the respiratory chain may turn out as effective strategy for combating M. tuberculosis.
Journal ArticleDOI
Targeting bacterial energetics to produce new antimicrobials
TL;DR: The role of bioenergetic systems in mycobacterial persistence is summarized and the multi-targeting nature of uncouplers and the place these molecules may have in future drug development are discussed.
Journal ArticleDOI
Molecular Hydrogen Metabolism: a Widespread Trait of Pathogenic Bacteria and Protists.
TL;DR: There is a rich literature on hydrogenases in growth, survival, and virulence in some pathogens, but a detailed understanding of H2 metabolism in most pathogens, especially obligately anaerobic bacteria, is lacking.
Journal ArticleDOI
Identification and validation of novel drug targets in Mycobacterium tuberculosis.
Vinayak Singh,Valerie Mizrahi +1 more
TL;DR: Some of the key advances that have enabled the strengths of target-led and phenotypic approaches to TB drug discovery to be harnessed both independently and in combination are highlighted.
References
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Koen Andries,Peter Verhasselt,Jerome Guillemont,Hinrich W. H. Göhlmann,Jean-Marc Neefs,Hans Winkler,Jef Van Gestel,Philip Timmerman,Min Zhu,Ennis Lee,Peter Williams,Didier de Chaffoy,Emma Huitric,Sven Hoffner,Emmanuelle Cambau,Chantal Truffot-Pernot,Nacer Lounis,Vincent Jarlier +17 more
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Journal ArticleDOI
A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis.
C. Kendall Stover,Paul Warrener,Donald R. VanDevanter,David R. Sherman,Taraq M. Arain,Michael H. Langhorne,Scott Anderson,J. Andrew Towell,Ying Yuan,David N. McMurray,Barry N. Kreiswirth,Clifton E. Barry,William R. Baker +12 more
TL;DR: It is concluded that nitroimidazopyrans offer the practical qualities of a small molecule with the potential for the treatment of tuberculosis and bactericidal activity against both replicating and static M. tuberculosis.
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