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New open source drug candidate series to explore, originating from GSK. We're looking at it, and anyone else is free to jump in. Promising initial data. Now seeking analogs. #tuberculosis  
In recognition of it being World TB day today, and to promote the development of urgently needed new medicines for this terrible disease I'd like to point people to a project they can be involved i...
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Matthew Todd
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News  - 
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Company is http://im4tb.org/, Stewart Cole
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New DNA sequencing method to diagnose #tuberculosis http://www.medaxs.com.au/mdxgridfeed/post/2/180802
Direct sequencing of DNA provides an alternative to the time-consuming culture of the bacteria that cause TB, shown here. Credit: Agarwal et al. (taken from Agarwal et al. Annals of Clinical Microbiology and Antimicrobials 2005 4:18 doi:10.1186/1476-0711-
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Is this project still active? This might be a better project for me as there is a known target 
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Not quite sure what you mean there, Mandrake - whether there's a target depends on the drug... But in any case, it's as active as you'd like to make it. I'll have a postdoc starting in the lab in a few weeks who'll be doing TB research, and we'll post here, but these pages are a forum for anyone to post results or ideas.
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Matthew Todd
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Evidence SQ109 targets MmpL3 10.1128/AAC.05708-11 "SQ109, a 1,2-diamine related to ethambutol, is currently in clinical trials for the treatment of tuberculosis, but its mode of action remains unclear. Here, we demonstrate that SQ109 disrupts cell wall assembly, as evidenced by macromolecular incorporation assays and ultrastructural analyses. SQ109 interferes with the assembly of mycolic acids into the cell wall core of Mycobacterium tuberculosis, as bacilli exposed to SQ109 show immediate inhibition of trehalose dimycolate (TDM) production and fail to attach mycolates to the cell wall arabinogalactan. These effects were not due to inhibition of mycolate synthesis, since total mycolate levels were unaffected, but instead resulted in the accumulation of trehalose monomycolate (TMM), the precursor of TDM and cell wall mycolates. In vitro assays using purified enzymes showed that this was not due to inhibition of the secreted Ag85 mycolyltransferases. We were unable to achieve spontaneous generation of SQ109-resistant mutants; however, analogs of this compound that resulted in similar shutdown of TDM synthesis with concomitant TMM accumulation were used to spontaneously generate resistant mutants that were also cross-resistant to SQ109. Whole-genome sequencing of these mutants showed that these all had mutations in the essential mmpL3 gene, which encodes a transmembrane transporter. Our results suggest that MmpL3 is the target of SQ109 and that MmpL3 is a transporter of mycobacterial TMM."
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Matthew Todd
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Nice review on TB drug discovery. "The expectation that genomics would result in new therapeutic interventions for infectious diseases remains unfulfilled. In the post‐genomic era, the decade immediately following the availability of the genome sequence of Mycobacterium tuberculosis, tuberculosis (TB) drug discovery relied heavily on the target‐based approach but this proved unsuccessful leading to a return to whole cell screening. Genomics underpinned screening by providing knowledge and many enabling technologies, most importantly whole genome resequencing to find resistance mutations and targets, and this resulted in a selection of leads and new TB drug candidates that are reviewed here. Unexpectedly, many new targets were found to be ‘promiscuous’ as they were inhibited by a variety of different compounds. In the post‐post‐genomics era, more advanced technologies have been implemented and these include high‐content screening, screening for inhibitors of latency, the use of conditional knock‐down mutants for validated targets and siRNA screens. In addition, immunomodulation and pharmacological manipulation of host functions are being explored in an attempt to widen our therapeutic options."
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"Selecting and translating in vitro leads for a disease into molecules with in vivo activity in an animal model of the disease is a challenge that takes considerable time and money. As an example, recent years have seen whole-cell phenotypic screens of millions of compounds yielding over 1500 inhibitors of Mycobacterium tuberculosis (Mtb). These must be prioritized for testing in the mouse in vivo assay for Mtb infection, a validated model utilized to select compounds for further testing. We demonstrate learning from in vivo active and inactive compounds using machine learning classification models (Bayesian, support vector machines, and recursive partitioning) consisting of 773 compounds. The Bayesian model predicted 8 out of 11 additional in vivo actives not included in the model as an external test set. Curation of 70 years of Mtb data can therefore provide statistically robust computational models to focus resources on in vivo active small molecule antituberculars. This highlights a cost-effective predictor for in vivo testing elsewhere in other diseases."
A; Accounts of Chemical Research · ACS Applied Materials & Interfaces · ACS Catalysis · ACS Chemical Biology · ACS Chemical Neuroscience · ACS Combinatorial Science · - Journal of Combinatorial Chemistry · ACS Macro Letters · ACS Medicinal Chemistry Letters · ACS Nano · ACS Photonics ...
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Matthew Todd
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Paper from 2011 on crowdsourcing desirability of compound classes - similar to some things we've been doing in +Open Source Malaria of late, and which will doubtless arise in other disease areas like TB.
A; Accounts of Chemical Research · ACS Applied Materials & Interfaces · ACS Catalysis · ACS Chemical Biology · ACS Chemical Neuroscience · ACS Combinatorial Science · - Journal of Combinatorial Chemistry · ACS Macro Letters · ACS Medicinal Chemistry Letters · ACS Nano · ACS Photonics ...
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About this community

Any aspect of TB research that is open source. (Community image created with http://en.wikipedia.org/wiki/File:TB_in_sputum.png)
March 24th is World Tuberculosis (TB) day. The purpose of this day is to raise awareness about the TB epidemic and to support all control efforts around the world. This yearly event signifies the d...
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Explain TB brings vital medical information about tuberculosis and its trea...
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Timing of food intake could impact effectiveness of #tuberculosis treatment http://www.medaxs.com.au/mdxgridfeed/post/2/155001
The timing of food intake in the early phase of tuberculosis treatment could have a negative impact on the effectiveness of TB treatment.
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Matthew Todd
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Evidence another compound, BM212, also targets MmpL3. 10.1128/AAC.05270-11.  "The 1,5-diarylpyrrole derivative BM212 was previously shown to be active against multidrug-resistant clinical isolates and Mycobacterium tuberculosis residing within macrophages as well as against Mycobacterium avium and other atypical mycobacteria. To determine its mechanism of action, we identified the cellular target. Spontaneous Mycobacterium smegmatis, Mycobacterium bovis BCG, and M. tuberculosis H37Rv mutants that were resistant to BM212 were isolated. By the screening of genomic libraries and by whole-genome sequencing, we found that all the characterized mutants showed mutations in the mmpL3 gene, allowing us to conclude that resistance to BM212 maps to the MmpL3 protein, a member of the MmpL (mycobacterial membrane protein, large) family. Susceptibility was unaffected by the efflux pump inhibitors reserpine, carbonylcyanide m-chlorophenylhydrazone, and verapamil. Uptake/efflux experiments with [14C]BM212 demonstrated that resistance is not driven by the efflux of BM212. Together, these data strongly suggest that the MmpL3 protein is the cellular target of BM212."
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Matthew Todd
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More compounds hitting MmpL3 (AU1235) 10.1038/nchembio.794 "New chemotherapeutics active against multidrug-resistant Mycobacterium tuberculosis are urgently needed. We report on the identification of an adamantyl urea compound that shows potent bactericidal activity against M. tuberculosis and a unique mode of action, namely the abolition of the translocation of mycolic acids from the cytoplasm, where they are synthesized to the periplasmic side of the plasma membrane and are in turn transferred onto cell wall arabinogalactan or used in the formation of virulence-associated, outer membrane, trehalose-containing glycolipids. Whole-genome sequencing of spontaneous-resistant mutants of M. tuberculosis selected in vitro followed by genetic validation experiments revealed that our prototype inhibitor targets the inner membrane transporter MmpL3. Conditional gene expression of mmpL3 in mycobacteria and analysis of inhibitor-treated cells validate MmpL3 as essential for mycobacterial growth and support the involvement of this transporter in the translocation of trehalose monomycolate across the plasma membrane." http://www.nature.com/nchembio/journal/v8/n4/full/nchembio.794.html
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Matthew Todd
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Compounds from the Broad Institute that also target MmpL3. "Despite the urgent need for new antitubercular drugs, few are on the horizon. To combat the problem of emerging drug resistance, structurally unique chemical entities that inhibit new targets will be required. Here we describe our investigations using whole cell screening of a diverse collection of small molecules as a methodology for identifying novel inhibitors that target new pathways for Mycobacterium tuberculosis drug discovery. We find that conducting primary screens using model mycobacterial species may limit the potential for identifying new inhibitors with efficacy against M. tuberculosis. In addition, we confirm the importance of developing in vitro assay conditions that are reflective of in vivo biology for maximizing the proportion of hits from whole cell screening that are likely to have activity in vivo. Finally, we describe the identification and characterization of two novel inhibitors that target steps in M. tuberculosis cell wall biosynthesis. The first is a novel benzimidazole that targets mycobacterial membrane protein large 3 (MmpL3), a proposed transporter for cell wall mycolic acids. The second is a nitro-triazole that inhibits decaprenylphosphoryl-β-d-ribose 2′-epimerase (DprE1), an epimerase required for cell wall biosynthesis. These proteins are both among the small number of new targets that have been identified by forward chemical genetics using resistance generation coupled with genome sequencing. This suggests that methodologies currently employed for screening and target identification may lead to a bias in target discovery and that alternative methods should be explored."
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Indoleamides compounds active against MmpL3. Paywall, though. DOI: 10.1038/ncomms3907 "Responsible for nearly two million deaths each year, the infectious disease tuberculosis remains a serious global health challenge. The emergence of multidrug- and extensively drug-resistant strains of Mycobacterium tuberculosis confounds control efforts, and new drugs with novel molecular targets are desperately needed. Here we describe lead compounds, the indoleamides, with potent activity against both drug-susceptible and drug-resistant strains of M. tuberculosis by targeting the mycolic acid transporter MmpL3. We identify a single mutation in mmpL3, which confers high resistance to the indoleamide class while remaining susceptible to currently used first- and second-line tuberculosis drugs, indicating a lack of cross-resistance. Importantly, an indoleamide derivative exhibits dose-dependent antimycobacterial activity when orally administered to M. tuberculosis-infected mice. The bioavailability of the indoleamides, combined with their ability to kill tubercle bacilli, indicates great potential for translational developments of this structure class for the treatment of drug-resistant tuberculosis."
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"The report of a meeting to discuss potential 2014/15 funding priorities on tuberculosis and other mycobacterial infections for the European and Developing Countries Clinical Trials Partnership (EDCTP) has been published. The core recommendations, which were developed at a October, 2013 stakeholder meeting in Paris, are summarized into the themes of diagnostics, vaccines, treatment, control and implementation strategies, and partnerships"
The report of a meeting to discuss potential 2014/15 funding priorities on tuberculosis and other mycobacterial infections for the European and Developing Countries Clinical Trials Partnership (EDCTP) has been published. The core recommendations, which were developed at a October, ...
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Matthew Todd
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Target prediction for the open GSK TB set, authors include +John Overington 
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