Journal ArticleDOI
Why are membrane targets discovered by phenotypic screens and genome sequencing in Mycobacterium tuberculosis
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TLDR
Key recommendations are made regarding follow-up of the hydrophobic leads recently discovered using phenotypic screening and target elucidation by genome sequencing, and consideration is given to the properties of small molecule screening libraries.About:
This article is published in Tuberculosis.The article was published on 2013-11-01. It has received 85 citations till now. The article focuses on the topics: Phenotypic screening & Drug discovery.read more
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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.
Journal ArticleDOI
The Tuberculosis Drug Discovery and Development Pipeline and Emerging Drug Targets
TL;DR: This review summarizes the current TB drug development pipeline and proposes strategies for generating improved hits and leads in the discovery phase that could help achieve the goal of better, shorter, safer TB drug regimens with utility against drug-sensitive and drug-resistant disease.
Journal ArticleDOI
Novel Insights into the Mechanism of Inhibition of MmpL3, a Target of Multiple Pharmacophores in Mycobacterium tuberculosis
Wei Li,Ashutosh Upadhyay,Fabio L. Fontes,E. Jeffrey North,Yuehong Wang,Debbie C. Crans,Anna E. Grzegorzewicz,Victoria Jones,Scott G. Franzblau,Richard E. Lee,Dean C. Crick,Mary Jackson +11 more
TL;DR: The results indicate that the inhibitory effects of adamantyl ureas, indolecarboxamides, tetrahydropyrazolopyrimidines, and the 1,5-diarylpyrrole BM212 on the transport activity of MmpL3 in actively replicating M. tuberculosis bacilli are the first explanation for the large number of pharmacophores that apparently target this essential inner membrane transporter.
Journal ArticleDOI
Antiinfectives targeting enzymes and the proton motive force
Xinxin Feng,Wei Zhu,Lici A. Schurig-Briccio,Steffen Lindert,Carolyn Shoen,Reese Hitchings,Jikun Li,Yang Wang,Noman Baig,Tianhui Zhou,Boo Kyung Kim,Dean C. Crick,Michael H. Cynamon,J. Andrew McCammon,Robert B. Gennis,Eric Oldfield +15 more
TL;DR: It is shown that some FDA-approved drugs, such as clofazimine, clomiphene, and bedaquiline, with antiinfective activity act as uncouplers, and that screening for combined enzyme inhibition plus uncoupler activity will lead to new antibiotic leads.
Journal ArticleDOI
Respiratory Flexibility in Response to Inhibition of Cytochrome c Oxidase in Mycobacterium tuberculosis
Kriti Arora,Bernardo Ochoa-Montaño,Patricia S. Tsang,Tom L. Blundell,Stephanie S. Dawes,Valerie Mizrahi,Valerie Mizrahi,Tracy Bayliss,Claire J. MacKenzie,Laura A. T. Cleghorn,Peter C. Ray,Paul G. Wyatt,Eugene Uh,Jinwoo Lee,Clifton E. Barry,Helena I. Boshoff +15 more
TL;DR: A series of five chemically diverse scaffolds that have in vitro activities on replicating and hypoxic nonreplicating bacilli by targeting the respiratory bc1 complex in Mycobacterium tuberculosis in a strain-dependent manner highlight the promiscuity of the bc1complex and the risk of targeting energy metabolism with new drugs.
References
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Journal ArticleDOI
Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings
TL;DR: Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described in this article, where the rule of 5 is used to predict poor absorption or permeability when there are more than 5 H-bond donors, 10 Hbond acceptors, and the calculated Log P (CLogP) is greater than 5 (or MlogP > 415).
Journal ArticleDOI
Molecular properties that influence the oral bioavailability of drug candidates.
Daniel F. Veber,Stephen R. Johnson,Hung-Yuan Cheng,Brian R. Smith,Keith W. Ward,Kenneth D. Kopple +5 more
TL;DR: Reduced molecular flexibility, as measured by the number of rotatable bonds, and low polar surface area or total hydrogen bond count are found to be important predictors of good oral bioavailability, independent of molecular weight.
Journal ArticleDOI
Genes required for mycobacterial growth defined by high density mutagenesis
TL;DR: The use of transposon site hybridization (TraSH) is described to comprehensively identify the genes required by the causative agent, Mycobacterium tuberculosis, for optimal growth, suggesting that the minimal gene set required for survival varies greatly between organisms with different evolutionary histories.
Journal ArticleDOI
Strong Inference: Certain systematic methods of scientific thinking may produce much more rapid progress than others
TL;DR: Weinberg as mentioned in this paper pointed out that some fields of science are moving forward very much faster than others, perhaps by an order of magnitude, if numbers could be put on such estimates.
Certain systematic methods of scientific thinking may produce much more rapid progress than others.
TL;DR: Anyone who looks at the matter closely will agree that some fields of science are moving forward very much faster than others, perhaps by an order of magnitude, if numbers could be put on such estimates.
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