Browsing by Subject "Tuberculosis drug discovery"

Now showing 1 - 3 of 3
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    Identification of new drug targets and resistance mechanisms in Mycobacterium tuberculosis
    (Public Library of Science, 2013) Ioerger, Thomas R; O'Malley, Theresa; Liao, Reiling; Guinn, Kristine M; Hickey, Mark J; Mohaideen, Nilofar; Murphy, Kenan C; Boshoff, Helena I M; Mizrahi, Valerie; Rubin, Eric J
    Identification of new drug targets is vital for the advancement of drug discovery against Mycobacterium tuberculosis , especially given the increase of resistance worldwide to first- and second-line drugs. Because traditional target-based screening has largely proven unsuccessful for antibiotic discovery, we have developed a scalable platform for target identification in M. tuberculosis that is based on whole-cell screening, coupled with whole-genome sequencing of resistant mutants and recombineering to confirm. The method yields targets paired with whole-cell active compounds, which can serve as novel scaffolds for drug development, molecular tools for validation, and/or as ligands for co-crystallization. It may also reveal other information about mechanisms of action, such as activation or efflux. Using this method, we identified resistance-linked genes for eight compounds with anti-tubercular activity. Four of the genes have previously been shown to be essential: AspS, aspartyl-tRNA synthetase, Pks13, a polyketide synthase involved in mycolic acid biosynthesis, MmpL3, a membrane transporter, and EccB3, a component of the ESX-3 type VII secretion system. AspS and Pks13 represent novel targets in protein translation and cell-wall biosynthesis. Both MmpL3 and EccB3 are involved in membrane transport. Pks13, AspS, and EccB3 represent novel candidates not targeted by existing TB drugs, and the availability of whole-cell active inhibitors greatly increases their potential for drug discovery.
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    Patient Adherence to Tuberculosis Treatment: A Systematic Review of Qualitative Research
    (Public Library of Science, 2007) Munro, Salla A; Lewin, Simon A; Smith, Helen J; Engel, Mark E; Fretheim, Atle; Volmink, Jimmy
    From a systematic review of qualitative research, Munro and coauthors found that a range of interacting factors can lead to patients deciding not to complete their course of tuberculosis treatment.
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    Shared air: a renewed focus on ventilation for the prevention of tuberculosis transmission
    (Public Library of Science, 2014) Richardson, Eugene T; Morrow, Carl D; Kalil, Darryl B; Bekker, Linda-Gail; Wood, Robin
    BACKGROUND: Despite an improvement in the overall TB cure rate from 40-74% between 1995 and 2011, TB incidence in South Africa continues to increase. The epidemic is notably disquieting in schools because the vulnerable population is compelled to be present. Older learners (age 15-19) are at particular risk given a smear-positive rate of 427 per 100,000 per year and the significant amount of time they spend indoors. High schools are therefore important locations for potential TB infection and thus prevention efforts. Methods and FINDINGS: Using portable carbon dioxide monitors, we measured CO 2 in classrooms under non-steady state conditions. The threshold for tuberculosis transmission was estimated using a carbon dioxide-based risk equation. We determined a critical rebreathed fraction of carbon dioxide ( ) of 1·6%, which correlates with an indoor CO 2 concentration of 1000 ppm. These values correspond with a ventilation rate of 8·6 l/s per person or 12 air exchanges per hour (ACH) for standard classrooms of 180 m 3 . CONCLUSIONS: Given the high smear positive rate of high-school adolescents in South Africa, the proposal to achieve CO 2 levels of 1000ppm through natural ventilation (in the amount 12 ACH) will not only help achieve WHO guidelines for providing children with healthy indoor environments, it will also provide a low-cost intervention for helping control the TB epidemic in areas of high prevalence.