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
TLDR
The synthesis and characterization of 1,3-benzothiazin-4-ones (BTZs), a new class of antimycobacterial agents that kill Mycobacterium tuberculosis in vitro, ex vivo, and in mouse models of TB are described.Abstract:
New drugs are required to counter the tuberculosis (TB) pandemic. Here, we describe the synthesis and characterization of 1,3-benzothiazin-4-ones (BTZs), a new class of antimycobacterial agents that kill Mycobacterium tuberculosis in vitro, ex vivo, and in mouse models of TB. Using genetics and biochemistry, we identified the enzyme decaprenylphosphoryl-beta-d-ribose 2'-epimerase as a major BTZ target. Inhibition of this enzymatic activity abolishes the formation of decaprenylphosphoryl arabinose, a key precursor that is required for the synthesis of the cell-wall arabinans, thus provoking cell lysis and bacterial death. The most advanced compound, BTZ043, is a candidate for inclusion in combination therapies for both drug-sensitive and extensively drug-resistant TB.read more
Citations
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疟原虫var基因转换速率变化导致抗原变异[英]/Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A
TL;DR: PfPMP1)与感染红细胞、树突状组胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作�ly.
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The challenge of new drug discovery for tuberculosis
TL;DR: In this review, innovations in TB drug discovery and evolving strategies to bring newer agents more quickly to patients are discussed.
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Advances in the development of new tuberculosis drugs and treatment regimens
TL;DR: Current concepts and recent advances in TB drug discovery and development are covered, including an update of ongoing TB treatment trials, newer clinical trial designs, TB biomarkers and adjunct host-directed therapies.
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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
TL;DR: 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.
Journal ArticleDOI
Molecular basis and mechanisms of drug resistance in Mycobacterium tuberculosis: classical and new drugs.
TL;DR: This article presents an updated review of the mechanisms and molecular basis of drug resistance in M. tuberculosis and comments on the several gaps in current knowledge of the molecular mechanisms of drug Resistance to the main classical and new anti-TB drugs.
References
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疟原虫var基因转换速率变化导致抗原变异[英]/Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A
TL;DR: PfPMP1)与感染红细胞、树突状组胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作�ly.
Journal ArticleDOI
Bacterial Persistence as a Phenotypic Switch
Nathalie Q. Balaban,Nathalie Q. Balaban,Jack Merrin,Remy Chait,Lukasz Kowalik,Stanislas Leibler +5 more
TL;DR: Investigating the persistence of single cells of Escherichia coli with the use of microfluidic devices found phenotypic switching occurred between normally growing cells and persister cells having reduced growth rates, leading to a simple mathematical description of the persistence switch.
Journal ArticleDOI
A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis.
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
TL;DR: A diarylquinoline, R207910, is identified that potently inhibits both drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro and mutants selected in vitro suggest that the drug targets the proton pump of adenosine triphosphate (ATP) synthase.
Journal ArticleDOI
Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa
Neel R. Gandhi,Neel R. Gandhi,Anthony P. Moll,A. Willem Sturm,Robert Pawinski,Thiloshini Govender,Umesh G. Lalloo,Kimberly Zeller,Kimberly Zeller,Jason R. Andrews,Gerald Friedland +10 more
TL;DR: MDR tuberculosis is more prevalent than previously realised in a rural area in KwaZulu Natal, South Africa and has been transmitted to HIV co-infected patients and is associated with high mortality.
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Global epidemiology of tuberculosis.
TL;DR: African region has the highest estimated incidence rate but the majority of patients with tuberculosis live in the most populous countries of Asia; Bangladesh China India Indonesia and Pakistan together account for half (48%) the new cases that arise every year.
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