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S-Enantiomer of the Antitubercular Compound S006-830 Complements Activity of Frontline TB Drugs and Targets Biogenesis of Mycobacterium tuberculosis Cell Envelope.

ABSTRACT: A synthetic molecule S006-830, belonging to the class of thiophene-containing trisubstituted methanes, had shown good in vitro and in vivo bactericidal activity against drug-sensitive and drug-resistant Mycobacterium tuberculosis (Mtb). The molecule had also shown good druglike pharmacokinetic properties. However, S006-830 is a racemic mixture of two enantiomers, one of which could possess a better pharmacological profile than the other. We purified both the enantiomers on a chiral column and observed that S-enantiomer has a significantly higher inhibitory and cidal activity against Mtb than the R-enantiomer. Action of S-S006-830 was "synergistic" for rifampicin and "additive" for isoniazid and ethambutol. The combination of S-S006-830 and rifampicin produced 100% kill of Mtb within 8 days. In a chemical proteomics approach using matrix-bound compound to pull down its target protein(s) from Mtb membrane, FabG4 (β-ketoacyl CoA reductase, EC 1.1.1.100) emerged as the most likely target for S-S006-830. In target validation assays, the compound exhibited 2-fold higher inhibitory concentration for an Mtb construct overexpressing FabG4. In addition, it inhibited mycolic acid biosynthesis and formation of biofilms by Mtb. Molecular docking of S-S006-830 with FabG4 was consistent with the experimental data. These results support the development of S-S006-830 as a novel lead against tuberculosis.

SUBMITTER: Singh P

PROVIDER: S-EPMC6045410 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: Plant growth is a complex process involving cell division and elongation. Arabidopsis thaliana hypocotyls undergo a 100-fold length increase mainly by cell elongation. Cell enlargement implicates significant changes in the composition and structure of the cell wall. In order to understand cell wall biogenesis during cell elongation, mRNA profiling was made on half- (active elongation) and fully-grown (after growth arrest) etiolated hypocotyls. RESULTS: Transcriptomic analysis was focused on two sets of genes. The first set of 856 genes named cell wall genes (CWGs) included genes known to be involved in cell wall biogenesis. A significant proportion of them has detectable levels of transcripts (55.5%), suggesting that these processes are important throughout hypocotyl elongation and after growth arrest. Genes encoding proteins involved in substrate generation or in synthesis of polysaccharides, and extracellular proteins were found to have high transcript levels. A second set of 2927 genes labeled secretory pathway genes (SPGs) was studied to search for new genes encoding secreted proteins possibly involved in wall expansion. Based on transcript level, 433 genes were selected. Genes not known to be involved in cell elongation were found to have high levels of transcripts. Encoded proteins were proteases, protease inhibitors, proteins with interacting domains, and proteins involved in lipid metabolism. In addition, 125 of them encoded proteins with yet unknown function. Finally, comparison with results of a cell wall proteomic study on the same material revealed that 48 out of the 137 identified proteins were products of the genes having high or moderate level of transcripts. About 15% of the genes encoding proteins identified by proteomics showed levels of transcripts below background. CONCLUSION: Members of known multigenic families involved in cell wall biogenesis, and new genes that might participate in cell elongation were identified. Significant differences were shown in the expression of such genes in half- and fully-grown hypocotyls. No clear correlation was found between the abundance of transcripts (transcriptomic data) and the presence of the proteins (proteomic data) demonstrating (i) the importance of post-transcriptional events for the regulation of genes during cell elongation and (ii) that transcriptomic and proteomic data are complementary.

Project description:BackgroundOver the past decade, global health policy has increased its focus on measures to halt further increase in tuberculosis (TB) incidence and management of diabetes mellitus (DM). However, the vertical management of these two diseases have not achieved much in addressing the adverse effects of the rising tuberculosis-diabetes co-epidemic. This necessitated the World Health Organisation and the International Union Against Tuberculosis and Lung Disease to develop a framework to manage this dual disease burden. TB-DM co-epidemic is a public health concern in Ghana, adversely threatening the country's fragile health systems. Since frontline healthcare workers are critical in health policy implementation, this study used Lipsky's theoretical framework of street-level bureaucracy to explore their experiences in implementing the collaborative framework at the health facility level in Ghana.MethodsThis qualitative study was conducted between July to September 2019 using an exploratory design. Data was generated using a semi-structured interview guide designed to elicit information on knowledge of TB-DM comorbidity as well as systems for co-management. Twenty-three in-depth interviews were conducted among purposively selected frontline healthcare workers (doctors, nurses, TB task- shifting officers, TB institutional coordinators and hospital managers) from three health facilities in the Northern Region of Ghana. The lead author also conducted observations and document reviews, in order to fully address the study objectives. Thematic analysis was guided by the Lipsky's theoretical framework of street level bureaucracy.ResultsThe findings revealed three main themes and six sub-themes. Main themes were Prioritisation of TB/HIV co-infection while negating TB-DM comorbidity, Poor working conditions, and Coping mechanisms, whereas sub-themes were Low knowledge and awareness of TB-DM comorbidity, Limited awareness of the collaborative framework, High workload in TB & DM Clinics, Multiple roles, Inadequate training, and Space shortage.ConclusionsFrontline healthcare workers had limited knowledge of TB-DM comorbidity and the collaborative framework, which, in turn adversely affected the effectiveness in implementing the framework. The effective implementation of the framework begins with raising awareness about the framework through in service training amongst the frontline healthcare workers. Additionally, an integrated screening tool to detect both TB and DM would help achieve early detection of TB-DM comorbidity.

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S-Enantiomer of the Antitubercular Compound S006-830 Complements Activity of Frontline TB Drugs and Targets Biogenesis of Mycobacterium tuberculosis Cell Envelope.

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