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
Reads0
Chats0
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
Citations
More filters
Journal ArticleDOI
Antibacterial drug discovery in the resistance era
Eric D. Brown,Gerard D. Wright +1 more
TL;DR: The looming antibiotic-resistance crisis has penetrated the consciousness of clinicians, researchers, policymakers, politicians and the public at large as discussed by the authors, and the evolution and widespread distribution of antibiotic-resistant elements in bacterial pathogens has made diseases that were once easily treatable deadly again.
Journal ArticleDOI
Hit and lead criteria in drug discovery for infectious diseases of the developing world
Kei Katsuno,Jeremy N. Burrows,Ken Duncan,Rob Hooft van Huijsduijnen,Takushi Kaneko,Kiyoshi Kita,Charles E. Mowbray,Dennis Schmatz,Peter Warner,B. T. Slingsby +9 more
TL;DR: The Japanese Global Health Innovative Technology (GHIT) Fund convened with experts from the Medicines for Malaria Venture, the Drugs for Neglected Diseases initiative and the TB Alliance, together with representatives from the Bill &Melinda Gates Foundation, to set disease-specific criteria for hits and leads for malaria, tuberculosis, visceral leishmaniasis and Chagas disease.
Journal ArticleDOI
New antituberculosis drugs, regimens, and adjunct therapies: needs, advances, and future prospects
Alimuddin Zumla,Alimuddin Zumla,Stephen H. Gillespie,Michael Hoelscher,Patrick P J Philips,Stewart T. Cole,Ibrahim Abubakar,Timothy D. McHugh,Marco Schito,Markus Maeurer,Andrew J. Nunn +10 more
TL;DR: The need to engage the community in design, implementation, and uptake of research is emphasised, to increase international cooperation between drug developers and health-care providers adopting new regimens.
Journal ArticleDOI
Antibiotics in the clinical pipeline at the end of 2015
TL;DR: There is growing global recognition that the continued emergence of multidrug-resistant bacteria poses a serious threat to human health and action plans released by the World Health Organization and governments of the UK and USA in particular recognize that discovering new antibiotics, particularly those with new modes of action, is one essential element required to avert future catastrophic pandemics.
Journal ArticleDOI
New agents for the treatment of drug-resistant Mycobacterium tuberculosis
TL;DR: The challenges to developing drugs to treat tuberculosis are discussed and how the field has adapted to these difficulties, with an emphasis on drug discovery approaches that might produce more effective agents and treatment regimens.
References
More filters
Journal ArticleDOI
Lipiarmycin targets RNA polymerase and has good activity against multidrug-resistant strains of Mycobacterium tuberculosis
Mekonnen Kurabachew,Stephen H. J. Lu,Philipp Krastel,Esther K. Schmitt,Bangalore L. Suresh,Anne Goh,John E. Knox,Ngai Ling Ma,Jan Jiricek,David Beer,Michael H. Cynamon,Frank Petersen,Véronique Dartois,Thomas H. Keller,Thomas Dick,Vasan K. Sambandamurthy +15 more
TL;DR: Lipiarmycin has excellent bactericidal activity against MTB and lacks cross-resistance to standard anti-TB drugs.
Patent
Anti-infective compounds
Zaesung No,Jaeseung Kim,Priscille Brodin,Min Jung Seo,Young-Mi Kim,Jonathan Cechetto,Heekyoung Jeon,Auguste Genovesio,Saeyeon Lee,Sunhee Kang,Fanny Anne Ewann,Ji Youn Nam,Thierry Christophe,Denis Philippe Cedric Fenistein,Heo Jamung,Jang Jiyeon +15 more
TL;DR: In this paper, the present invention relates to small molecule compounds and their use in the treatment of bacterial infections, in particular Tuberculosis, and is related to the present paper.
Journal ArticleDOI
Fast Standardized Therapeutic-Efficacy Assay for Drug Discovery against Tuberculosis
Joaquín Rullas,Juan Ignacio García,Manuela Beltran,Pere-Joan Cardona,Neus Cáceres,Jose F. Garcia-Bustos,Iñigo Angulo-Barturen +6 more
TL;DR: This assay is highly reproducible, allows good throughput, and was validated for drug lead optimization using isoniazid, rifampin, ethambutol, pyrazinamide, linezolid, and moxifloxacin.
Journal ArticleDOI
High-content imaging of Mycobacterium tuberculosis-infected macrophages: an in vitro model for tuberculosis drug discovery
TL;DR: A high-throughput and high-content workflow is described that allows large-scale screening of compound libraries in M. tuberculosis-infected macrophages and its utility for the development of new TB drugs is detailed.
Journal ArticleDOI
Activities of TMC207, Rifampin, and Pyrazinamide against Mycobacterium tuberculosis Infection in Guinea Pigs
Shaobin Shang,Crystal A. Shanley,Megan L. Caraway,Eileen A. Orme,Marcela Henao-Tamayo,Laurel Hascall-Dove,David F. Ackart,Anne J. Lenaerts,Randall J. Basaraba,Ian M. Orme,Diane J. Ordway +10 more
TL;DR: Data indicate that TMC207 could be a useful addition to current treatment regimens for tuberculosis, as shown by the new development of both pulmonary and extrapulmonary granulomatous lesions.
Related Papers (5)
A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis.
Benzothiazinones Kill Mycobacterium tuberculosis by Blocking Arabinan Synthesis
Vadim Makarov,Giulia Manina,Katarína Mikušová,Ute Möllmann,O. B. Ryabova,Brigitte Saint-Joanis,Neeraj Dhar,Maria Rosalia Pasca,Silvia Buroni,Anna Paola Lucarelli,Anna Milano,Edda De Rossi,Martina Belanova,Adela Bobovská,Petronela Dianišková,Jana Korduláková,Claudia Sala,Elizabeth Fullam,Patricia Schneider,John D. McKinney,Priscille Brodin,Thierry Christophe,Simon J. Waddell,Philip D. Butcher,Jakob Albrethsen,Ida Rosenkrands,Roland Brosch,Vrinda Nandi,Sowmya Bharath,Sheshagiri Gaonkar,Radha Shandil,V. Balasubramanian,Tanjore S. Balganesh,Sandeep Tyagi,Jacques H. Grosset,Giovanna Riccardi,Stewart T. Cole +36 more