Genomics

Dataset Information

35

Transcriptional response of M. tuberculosis to AX-35 treatment


ABSTRACT: We report here lead optimisation efforts for molecule GW861072X, one of 177 leads published in a GSK-led phenotypic screening campaign by Balell et al. (2013), generating the AX series. Along with the parent compound AX-35, four other derivatives with mild to no cytotoxicity showed potent in vitro and ex vivo activity in infected THP-1 macrophages against M. tuberculosis. Isolation of resistant mutants to AX compounds in M. tuberculosis revealed mutations in the QcrB of the cytochrome bc1 oxidase, one of two terminal oxidases of the mycobacterial electron transport chain. Cross-resistance studies, transcriptomic analyses and bioenergetics flux assays provide further evidence of QcrB as the target of the AX compounds, and that AX compounds likely interact differently with the quinol binding pocket compared to other QcrB inhibitors. The transcriptomic and bioenergetic profiles obtained when M. tuberculosis was treated with AX-35 are similar to transcriptomic and respiratory signatures of other cytochrome bc1 oxidase inhibitors, whereby the pronounced role of the alternate terminal oxidase cytochrome bd in the respiratory adaptation of M. tuberculosis could be observed. Genes involved in utilisation and synthesis of triacylglycerol (TAG) were also additionally observed to be up-regulated with AX treatment, indicating a switch induced towards lipid metabolism under this particular stress. Overall design: To gain insight into the initial adaptive response of M. tuberculosis to AX-35 treatment, the transcriptomes of wild-type H37Rv exposed to AX-35 at 10x and 30x MIC for a duration of four hours were examined. Two biological replicates were used for each condition.

INSTRUMENT(S): Illumina HiSeq 2500 (Mycobacterium tuberculosis)

SUBMITTER: Andrej Benjak  

PROVIDER: GSE113683 | GEO | 2018-04-26

REPOSITORIES: GEO

Dataset's files

Source:
Action DRS
GSE113683_CountTable.txt.gz Txt
GSE113683_DESeq2_res_Ax35_10x_vs._WT.csv.gz Csv
GSE113683_DESeq2_res_Ax35_30x_vs._WT.csv.gz Csv
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Publications


New drugs are needed to control the current tuberculosis (TB) pandemic caused by infection with <i>Mycobacterium tuberculosis</i> We report here on our work with AX-35, an arylvinylpiperazine amide, and four related analogs, which are potent antitubercular agents <i>in vitro</i> All five compounds showed good activity against <i>M. tuberculosis</i> <i>in vitro</i> and in infected THP-1 macrophages, while displaying only mild cytotoxicity. Isolation and characterization of <i>M. tuberculosis</i>-  ...[more]

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