ABSTRACT: Whole genome sequencing reveals genetic heterogeneity and suggests the role of selective bottleneck in defining the population structure of Mycobacterium tuberculosis clinical isolates.
Project description:Heterogeneity and selective vulnerability are among the key features of the healthy and diseased brain. Cerebellum contains majority of brain cells, and is thought to be relatively uniform in structure. We explore heterogeneity in the context of healthy cerebellum and during selective vulnerability in cerebellar disease.
Project description:Transcriptional profiling of mycobacterium tuberculosis clinical isolates in China comparing extensively drug-resistant tuberculosis with drug sensitive one.
Project description:Transcriptional profiling of mycobacterium tuberculosis clinical isolates in China comparing extensively drug-resistant tuberculosis with drug sensitive one. The same condition experiment. The samples were from the different drug-resistant strains. Only one replicate.
Project description:The identification and validation of a small molecule's targets is a major bottleneck in the discovery process for tuberculosis antibiotics. Activity-based protein profiling (ABPP) is an efficient tool for determining a small molecul's targets within complex proteomes. However, how target inhibition relates to biological activity is often left unexplored. Here we studied the effects of 1,2,3-triazole ureas on Mycobacterium tuberculosis . After screening ~200 compounds, we focused on two inhibitors active against both exponentially replicating and hypoxia-induced drug-tolerant Mtb that form part of a four-compound structure-activity series. The compound with negligible activity revealed potential false positive targets not addressed in other ABPP studies. Biochemistry, computational docking, and morphological analysis confirmed that active compounds preferentially inhibit serine hydrolases with cell wall and lipid metabolism functions and that disruption of the cell wall underlies biological activity. Our findings showed that ABPP identifies the targets most likely relevant to a compound's antibacterial activity.
Project description:<p>Gene rv3722c of Mycobacterium tuberculosis is essential for in vitro growth, and encodes a putative pyridoxal phosphate-binding protein of unknown function. Here we use metabolomic, genetic and structural approaches to show that Rv3722c is the primary aspartate aminotransferase of M. tuberculosis, and mediates an essential but underrecognized role in metabolism: nitrogen distribution. Rv3722c deficiency leads to virulence attenuation in macrophages and mice. Our results identify aspartate biosynthesis and nitrogen distribution as potential species-selective drug targets in M. tuberculosis.</p>
Project description:This project involves RNA-Seq analysis of samples obtained from the Phase IIA clinical trial TB-019 (NCT01669096) which evaluated kinetics of response, safety, and immunogenicity of the GSK Mycobacterium tuberculosis (MTB) vaccine M72/AS01E (“GSK M72”). GSK M72 consists of the M72 recombinant fusion of Mycobacterium tuberculosis (MTB) proteins Rv0125 and Rv1196 in combination with the liposome, TLR4 ligand (MPL), and QS21 saponin adjuvant AS01E (Leroux-Roels et al., 2013).