(Mycobacterium tuberculosis AND drug use and) articles in PubMed
- Validation of CoaBC as a bactericidal target in the coenzyme A pathway of Mycobacterium tuberculosis. [Journal Article]
- ACS Infect Dis 2016 Sep 27AI
- Mycobacterium tuberculosis relies on its own ability to biosynthesise coenzyme A in order to meet the needs of the myriad enzymatic reactions that depend on this cofactor for activity. As such, the e...
Mycobacterium tuberculosis relies on its own ability to biosynthesise coenzyme A in order to meet the needs of the myriad enzymatic reactions that depend on this cofactor for activity. As such, the essential pantothenate and coenzyme A biosynthesis pathways have attracted attention as targets for tuberculosis drug development. To identify the optimal step for coenzyme A pathway disruption in M. tuberculosis, we constructed and characterised a panel of conditional knockdown mutants in coenzyme A pathway genes. Here, we report that silencing of coaBC was bactericidal in vitro whereas silencing of panB, panC or coaE was bacteriostatic over the same time course. Silencing of coaBC was likewise bactericidal in vivo, whether initiated at infection, or during either the acute or chronic stages of infection, confirming that CoaBC is required for M. tuberculosis to grow and persist in mice, and arguing against significant CoaBC bypass via transport and assimilation of host-derived pantetheine in this animal model. These results provide convincing genetic validation of CoaBC as a new bactericidal drug target.
- Structure-Activity Relationships of the MEPicides: N-Acyl and O-linked Analogs of FR900098 as Inhibitors of Dxr from Mycobacterium tuberculosis and Yersinia pestis. [Journal Article]
- ACS Infect Dis 2016 Sep 27AI
- Despite continued research efforts, the threat of drug resistance from a variety of bacteria continues to plague clinical communities. Discovery and validation of novel biochemical targets will facil...
Despite continued research efforts, the threat of drug resistance from a variety of bacteria continues to plague clinical communities. Discovery and validation of novel biochemical targets will facilitate development of new drugs to combat these organisms. The methylerythritol phosphate (MEP) pathway to make isoprene units is a biosynthetic pathway essential to many bacteria. We and others have explored inhibitors of the MEP pathway as novel antibacterial agents. Mycobacterium tuberculosis, the causative agent of tuberculosis, and Yersinia pestis, resulting in the plague or "black death," both rely on the MEP pathway for isoprene production. 1-Deoxy-D-xylulose 5-phosphate reductoisomerase (Dxr) catalyzes the first committed step in the MEP pathway. We examined two series of Dxr inhibitors based on the parent structure of the retrohydroxamate natural product FR900098. The compounds contain either an extended N-acyl or O-linked alkyl/aryl group, and are designed to act as bisubstrate inhibitors of the enzyme. While nearly all of the compounds inhibited both Mtb and Yp Dxr to some extent, compounds generally displayed more potent inhibition against the Yp homolog, with the best analogs displaying nM IC50 values. In bacterial growth inhibition assays, the phosphonic acids generally resulted in poor antibacterial activity, likely a reflection of inadequate permeability. Accordingly, diethyl and diPOM prodrug esters of these compounds were made. While the added lipophilicity did not enhance Yersinia activity, the compounds showed significantly improved antitubercular activities. The most potent compounds have Mtb MIC values of 3-12 μg/mL. Taken together, we have uncovered two series of analogs that potently inhibit Dxr homologs from Mtb and Yp. These inhibitors of the MEP pathway, termed MEPicides, serve as leads for future analog development.
- Dataset generated using hyperplexing and click chemistry to monitor temporal dynamics of newly synthesized macrophage secretome post infection by mycobacterial strains. [Journal Article]
- Data Brief 2016; 9:349-54DB
- Here we provide data for SILAC and iTRAQ based hyperplexing combined with BONCAT based click chemistry for selective enrichment of newly synthesized proteins secreted by THP1 macrophages at various t...
Here we provide data for SILAC and iTRAQ based hyperplexing combined with BONCAT based click chemistry for selective enrichment of newly synthesized proteins secreted by THP1 macrophages at various time points after infection with four different strains of Mycobacterium tuberculosis. The macrophages were infected with H37Ra, H37Rv, BND433 and JAL2287 strains of M. tuberculosis. Newly-synthesized secreted host proteins were observed, starting from six hours post-infection till 26 h, at 4 h intervals. We have combined BONCAT with hyperplexing (18-plex), which blends SILAC and iTRAQ, for the first time. Two sets of triplex SILAC were used to encode the strains of M. tuberculosis - H37Ra & H37Rv in one and BND433 & JAL2287 in another with a control in each. BONCAT was used to enrich the secretome for newly synthesized proteins while 6-plex iTRAQ labeling was employed to quantify the temporal changes in the captured proteome. Each set of 18-plex was run in 4 MS replicates with two linear and two non-linear separation modes. This new variant of hyperplexing method, combining triplex SILAC with 6-plex iTRAQ, achieves 18-plex quantitation in a single MS run. Hyperplexing enables large scale spatio-temporal systems biology studies where large number of samples can be processed simultaneously and in quantitative manner. Data are available via ProteomeXchange with identifier ProteomeXchange: PXD004281.
- Inhibiting Mycobacterium tuberculosis within and without. [Review]
- Philos Trans R Soc Lond B Biol Sci 2016 Nov 5; 371(1707)PT
- Tuberculosis remains a scourge of global health with shrinking treatment options due to the spread of drug-resistant strains of Mycobacterium tuberculosis Intensive efforts have been made in the past...
Tuberculosis remains a scourge of global health with shrinking treatment options due to the spread of drug-resistant strains of Mycobacterium tuberculosis Intensive efforts have been made in the past 15 years to find leads for drug development so that better, more potent drugs inhibiting new targets could be produced and thus shorten treatment duration. Initial attempts focused on repurposing drugs that had been developed for other therapeutic areas but these agents did not meet their goals in clinical trials. Attempts to find new lead compounds employing target-based screens were unsuccessful as the leads were inactive against M. tuberculosis Greater success was achieved using phenotypic screening against live tubercle bacilli and this gave rise to the drugs bedaquiline, pretomanid and delamanid, currently in phase III trials. Subsequent phenotypic screens also uncovered new leads and targets but several of these targets proved to be promiscuous and inhibited by a variety of seemingly unrelated pharmacophores. This setback sparked an interest in alternative screening approaches that mimic the disease state more accurately. Foremost among these were cell-based screens, often involving macrophages, as these should reflect the bacterium's niche in the host more faithfully. A major advantage of this approach is its ability to uncover functions that are central to infection but not necessarily required for growth in vitro For instance, inhibition of virulence functions mediated by the ESX-1 secretion system severely attenuates intracellular M. tuberculosis, preventing intercellular spread and ultimately limiting tissue damage. Cell-based screens have highlighted the druggability of energy production via the electron transport chain and cholesterol metabolism. Here, I review the scientific progress and the pipeline, but warn against over-optimism due to the lack of industrial commitment for tuberculosis drug development and other socio-economic factors.This article is part of the themed issue 'The new bacteriology'.
- Identification and optimization of a new series of anti-tubercular quinazolinones. [Journal Article]
- Bioorg Med Chem Lett 2016 Sep 16BM
- A high throughput phenotypic screening against Mycobacterium smegmatis led us to the discovery of a new class of bacteriostatic, highly hydrophobic antitubercular quinazolinones that potently inhibit...
A high throughput phenotypic screening against Mycobacterium smegmatis led us to the discovery of a new class of bacteriostatic, highly hydrophobic antitubercular quinazolinones that potently inhibited the in vitro growth of either extracellular or intramacrophagic M. tuberculosis (Mtb), via modulation of an unidentified but yet novel target. Optimization of the initial hit compound culminated in the identification of potent but poorly soluble Mtb growth inhibitors, three of which were progressed to in vivo efficacy studies. Despite nanomolar in vitro potency and attractive PK properties, none of these compounds was convincingly potent in our in vivo mouse tuberculosis models. This lack of efficacy may be linked to the poor drug-likeness of the test molecules and/or to the properties of the target.
- Mycobacterium tuberculosis arylamine N-acetyltransferase acetylates and thus inactivates para-aminosalicylic acid. [Journal Article]
- Antimicrob Agents Chemother 2016 Sep 26AA
- Mycobacterium tuberculosis Arylamine N-acetyltransferase (TBNAT) is able to acetylate para-aminosalicylic acid (PAS) both in vitro and in vivo as determined by HPLC and ESI/MS techniques. Anti-tuberc...
Mycobacterium tuberculosis Arylamine N-acetyltransferase (TBNAT) is able to acetylate para-aminosalicylic acid (PAS) both in vitro and in vivo as determined by HPLC and ESI/MS techniques. Anti-tuberculosis activity of the acetylated PAS is significantly reduced. As a result, over-expression of TBNAT in M. tuberculosis results in PAS resistance, as determined by MIC tests and drug exposure experiments. Taken together, our results suggest that TBNAT from M. tuberculosis is able to inactivate PAS by acetylating the compound.
- Association between embB Codon 306 Mutations, Phenotypic Resistance Profiles and Genotypic Characterization in Clinical Mycobacterium tuberculosis Isolates from Hebei, China. [Journal Article]
- Antimicrob Agents Chemother 2016 Sep 26AA
- Ethambutol (EMB) is an essential first-line drug for tuberculosis (TB) treatment. Nucleotide substitutions at embB codon 306 have been proposed as a potential marker for EMB resistance and a predicto...
Ethambutol (EMB) is an essential first-line drug for tuberculosis (TB) treatment. Nucleotide substitutions at embB codon 306 have been proposed as a potential marker for EMB resistance and a predictor for broad drug resistance in clinical Mycobacterium tuberculosis (MTB) isolates. However, discordant findings about the association between embB306 mutation and EMB resistance were reported. The Hebei province is located in the Beijing-Tianjin-Hebei integration region; however, little information about the genetic diversity of embB locus is available in this area. In this study, we sequenced the region surrounding embB306 codon (codon 207-445) in 62 ethambutol-resistant (EMB(r)) isolates, 214 ethambutol-susceptible isolates but with resistance to other first-line drugs (EMB(s)) and 100 pan sensitive isolates. Our data indicated that none of pan sensitive isolates showed mutations at embB306 and 63 drug-resistant isolates harbored embB306 substitutions, with 56.5% (35/62) in EMB(r) isolates and 13.1% (28/214) in EMB(s) isolates. Significant association was observed between the embB306 mutation and resistance to INH, RIF, EMB and MDR, and the mutation rates of embB306 increased with increasing numbers of resistance to first-line drugs. The embB306 mutation is not the sole causative factor for EMB resistance and the poor sensitivity limits its utility as a marker for DR-TB. However, it may be a potential marker for broad resistance, especially for MDR. The MIRU-VNTR profiles may serve as a potential marker for predicting the possible embB306 substitutions that may occur in DR-TB isolates under antimicrobial selection pressure.
- Persistently high prevalence of primary resistance and multidrug resistance of tuberculosis in Heilongjiang Province, China. [Journal Article]
- BMC Infect Dis 2016; 16(1):516BI
- CONCLUSIONS: The high prevalence of drug resistant, MDR-TB, and fluoroquinolone-resistant MDR-TB is a big concern for TB control. More importantly, in order to control the development of MDR-TB effectively, we need to pay more attention to the primary resistance. Targeting reducing the prevalence of the risk factors may lead to better TB control in China.
- Verification of Frequency in Species of Nontuberculous Mycobacteria in Kermanshah Drinking Water Supplies Using the PCR-Sequencing Method. [Journal Article]
- Microb Drug Resist 2016 Sep 26MD
- CONCLUSIONS: In this study, we recognized the evidence of contamination by nontuberculous mycobacteria in corroded water pipes. As a result of the high prevalence of these bacteria in drinking water in Kermanshah, this is important evidence of transmission through drinking water. This finding can also help public health policy makers control these isolates in drinking water supplies in Kermanshah.
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- Recombinant Leishmania Rab6 (rLdRab6) is recognized by sera from visceral leishmaniasis patients. [Journal Article]
- Exp Parasitol 2016 Sep 22EP
- Rab proteins form the largest branch of the Ras superfamily. Rab proteins are key regulators of intracellular vesicular transport and membrane trafficking. Although RabGTPases are well-recognized tar...
Rab proteins form the largest branch of the Ras superfamily. Rab proteins are key regulators of intracellular vesicular transport and membrane trafficking. Although RabGTPases are well-recognized targets in human diseases but are under-explored therapeutically in the Leishmania parasite. Using a quantitative cytofluorimetric assay, we analyzed the composition and organization of Rab6GTPase protein which was found to be primarily localized on the parasite subpellicular membrane and flagellum due to its association with kinesin motor proteins in the cytoskeletal microtubules. Our aim was to also assess the diagnostic role of recombinant Rab6 protein from Leishmania donovani (rLdRab6) using sera/plasma of Indian visceral leishmaniasis (VL) patients. Receiver-operating characteristic (ROC) curve analysis indicated 100% sensitivity and 100% specificity for rLdRab6-based ELISA which was almost similar in comparison to recombinant K39-based ELISA (95.83% sensitivity and 100% specificity). Sera of patients from another intracellular pathogenic infection, Mycobacterium tuberculosis, did not contain any significant levels of anti-rLdRab6 antibody. Thus rLdRab6 accuracy in visceral leishmaniasis diagnosis makes it a promising antigen for clinical use.