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
Structure of Mycobacterium tuberculosis cytochrome bcc in complex with Q203 and TB47, two anti-TB drug candidates.
Shan Zhou,Weiwei Wang,Xiaoting Zhou,Yuying Zhang,Yuezheng Lai,Yanting Tang,Jinxu Xu,Dongmei Li,Jianping Lin,Xiaolin Yang,Ting Ran,Hongming Chen,Luke W. Guddat,Quan Wang,Yan Gao,Zihe Rao,Hongri Gong +16 more
TL;DR: In this article, the structures of Mycobacterium tuberculosis cytochrome bcc alone (2.68 A resolution) and in complex with clinical drug candidates Q203 and TB47 were determined by single-particle cryo-electron microscopy.
Posted ContentDOI
Nanoscaled discovery of a shunt rifamycin from Salinispora arenicola using a three-colour GFP-tagged Staphylococcus aureus macrophage infection assay
Nhan T. Pham,Joana Alves,Fiona Sargison,Reiko Cullum,Jan Wildenhain,William Fenical,Mark S. Butler,David A. Mead,Brendan M. Duggan,J. Ross Fitzgerald,James J. La Clair,Manfred Auer +11 more
TL;DR: In this paper , a confocal fluorescence imaging (CFI) was used to identify S. aureus-tagged macrophages as a front-line tool to identify antibiotic leads.
Journal ArticleDOI
On the Hunt for Next-Generation Antimicrobial Agents: An Online Symposium Organized Jointly by the French Society for Medicinal Chemistry (Société de Chimie Thérapeutique) and the French Microbiology Society (Société Française de Microbiologie) on 9–10 December 2021
K. Antraygues,Nina Compagne,Francesca Gisella Zoe Ruggieri,Kamel Djaout,Zainab Edoo,Maxime Eveque,Léo Faïon,Bruna Gioia,Salia Tangara,Anais Vieira Da Cruz,Baptiste Villemagne,Marion Flipo,Alain R. Baulard,Nicolas Willand +13 more
TL;DR: The symposium generated high-level scientific dialogue on the most recent advances in combating antimicrobial resistance and attracted more than 200 researchers from France and abroad with interests in drug discovery, antimicrobial Resistance, medicinal chemistry, and related disciplines.
TITLE: High-Content Screening (HCS) technology combined with a human granuloma
Mayra Silva-Miranda,Euloge Ekaza,Adrien Breiman,David Barros-Aguirre,Kevin Pethe,Fanny Anne Ewann,Lluís Ballell-Pages,Frédéric Altare +7 more
TL;DR: This study adapted HCS technology to investigate the activity of anti32 tubercular compounds in the context of an in vitro granuloma model and observed significant shifts in MIC50 between extracellular andgranuloma conditions.
Posted ContentDOI
Synthetic lethality of Mycobacterium tuberculosis NADH dehydrogenases is due to impaired NADH oxidation
TL;DR: In this paper , the authors provided insights into the biology of NADH dehydrogenases and a mechanistic explanation for Ndh-1/Ndh-2 synthetic lethality in Mycobacterium tuberculosis (Mtb).
References
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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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