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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In Vitro and In Vivo Activities of the Riminophenazine TBI-166 against Mycobacterium tuberculosis.
TL;DR: TBI-166 demonstrates activity at least equivalent to that of CFZ against intracellular M. tuberculosis and causes less skin discoloration than does CFZ despite its higher tissue accumulation, and warrants further study and potential clinical use.
Journal ArticleDOI
New drugs for the treatment of Mycobacterium tuberculosis infection.
TL;DR: The present methods of treating tuberculosis and novel anti-TB agents with their action method are talked about in order to advance awareness of these new compounds and medications.
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Biochemical and Structural Characterization of Mycobacterial Aspartyl-tRNA Synthetase AspS, a Promising TB Drug Target
Sudagar S. Gurcha,Veeraraghavan Usha,Jonathan A. G. Cox,Klaus Fütterer,Katherine A. Abrahams,Apoorva Bhatt,Luke J. Alderwick,Robert C. Reynolds,Nicholas J. Loman,Vijayashankar Nataraj,Carlos Alemparte,David Barros,Adrian J. Lloyd,Lluis Ballell,Judith V. Hobrath,Gurdyal S. Besra +15 more
TL;DR: The human pathogen Mycobacterium tuberculosis is the causative agent of pulmonary tuberculosis (TB), a disease with high worldwide mortality rates, and current treatment programs are under significant threat from multi-drug and extensively-drug resistant strains of M. tuberculosis, and it is essential to identify new inhibitors and their targets.
Journal ArticleDOI
Bacterial oxidases of the cytochrome bd family : redox enzymes of unique structure, function, and utility as drug targets
Vitaliy B. Borisov,Sergey A. Siletsky,Alessandro Paiardini,David Hoogewijs,Elena Forte,Alessandro Giuffrè,Robert K. Poole +6 more
TL;DR: It is clear that cytochrome bd is unique in its ability to confer resistance to toxic small molecules, a property that is significant for understanding the propensity of pathogens to possess this oxidase.
Journal ArticleDOI
Nitrofuranyl Methyl Piperazines as New Anti-TB Agents: Identification, Validation, Medicinal Chemistry, and PK Studies
Kushalava Reddy Yempalla,Gurunadham Munagala,Samsher Singh,Asmita Magotra,Sunil Kumar,Vikrant Singh Rajput,Sonali S. Bharate,Manoj Kumar Tikoo,Giriraj Singh,Inshad Ali Khan,Ram A. Vishwakarma,Parvinder Pal Singh +11 more
TL;DR: The rediscovery of a nitrofuranyl class of compounds with improved aqueous solubility and acceptable oral PK properties is presented, opening a new direction for further development.
References
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Journal ArticleDOI
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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
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