9 research outputs found
Identification of gene targets against dormant phase Mycobacterium tuberculosis infections
<p>Abstract</p> <p>Background</p> <p><it>Mycobacterium tuberculosis</it>, the causative agent of tuberculosis (TB), infects approximately 2 billion people worldwide and is the leading cause of mortality due to infectious disease. Current TB therapy involves a regimen of four antibiotics taken over a six month period. Patient compliance, cost of drugs and increasing incidence of drug resistant <it>M. tuberculosis </it>strains have added urgency to the development of novel TB therapies. Eradication of TB is affected by the ability of the bacterium to survive up to decades in a dormant state primarily in hypoxic granulomas in the lung and to cause recurrent infections.</p> <p>Methods</p> <p>The availability of <it>M. tuberculosis </it>genome-wide DNA microarrays has lead to the publication of several gene expression studies under simulated dormancy conditions. However, no single model best replicates the conditions of human pathogenicity. In order to identify novel TB drug targets, we performed a meta-analysis of multiple published datasets from gene expression DNA microarray experiments that modeled infection leading to and including the dormant state, along with data from genome-wide insertional mutagenesis that examined gene essentiality.</p> <p>Results</p> <p>Based on the analysis of these data sets following normalization, several genome wide trends were identified and used to guide the selection of targets for therapeutic development. The trends included the significant up-regulation of genes controlled by <it>devR</it>, down-regulation of protein and ATP synthesis, and the adaptation of two-carbon metabolism to the hypoxic and nutrient limited environment of the granuloma. Promising targets for drug discovery were several regulatory elements (<it>devR/devS</it>, <it>relA</it>, <it>mprAB</it>), enzymes involved in redox balance and respiration, sulfur transport and fixation, pantothenate, isoprene, and NAD biosynthesis. The advantages and liabilities of each target are discussed in the context of enzymology, bacterial pathways, target tractability, and drug development.</p> <p>Conclusion</p> <p>Based on our bioinformatics analysis and additional discussion of in-depth biological rationale, several novel anti-TB targets have been proposed as potential opportunities to improve present therapeutic treatments for this disease.</p
Effect of Atilmotin, a Motilin Receptor Agonist, on Esophageal, Lower Esophageal Sphincter, and Gastric Pressures
Modeling the Kinetics of the Permeation of Antibacterial Agents into Growing Bacteria and Its Interplay with Efflux
The FDA-approved anti-cancer drugs, streptozotocin and floxuridine, reduce the virulence of Staphylococcus aureus
Anthelmintic closantel enhances bacterial killing of polymyxin B against multidrug-resistant Acinetobacter baumannii
Repurposing Salicylanilide Anthelmintic Drugs to Combat Drug Resistant Staphylococcus aureus
The Effect of the Potential PhoQ Histidine Kinase Inhibitors on Shigella flexneri Virulence
Ghrelin and motilin receptors as drug targets for gastrointestinal disorders
G.J.S. is currently in receipt of a student CASE award from the British Biotechnology Science Research Council, sponsored by GlaxoSmithKline, and receives research funding from Takeda Pharmaceuticals