|
| Status |
Public on Apr 26, 2018 |
| Title |
Transcriptional response of M. tuberculosis to AX-35 treatment |
| Organism |
Mycobacterium tuberculosis |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
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.
|
| |
|
| Contributor(s) |
Benjak A, Foo CS, Cole ST |
| Citation(s) |
30301850 |
| |
| Submission date |
Apr 25, 2018 |
| Last update date |
Oct 17, 2018 |
| Contact name |
Andrej Benjak |
| E-mail(s) |
andrej.benjak@unibe.ch
|
| Organization name |
University of Bern
|
| Department |
Department for BioMedical Research
|
| Street address |
Murtenstrasse 24-28
|
| City |
Bern |
| ZIP/Postal code |
3008 |
| Country |
Switzerland |
| |
|
| Platforms (1) |
| GPL17879 |
Illumina HiSeq 2500 (Mycobacterium tuberculosis) |
|
| Samples (6)
|
| GSM3111057 |
M. tuberculosis wild-type, replicate 1 |
| GSM3111058 |
M. tuberculosis wild-type, replicate 2 |
| GSM3111059 |
M. tuberculosis exposed to Ax-35 at 10x MIC, replicate 1 |
| GSM3111060 |
M. tuberculosis exposed to Ax-35 at 10x MIC, replicate 2 |
| GSM3111061 |
M. tuberculosis exposed to Ax-35 at 30x MIC, replicate 1 |
| GSM3111062 |
M. tuberculosis exposed to Ax-35 at 30x MIC, replicate 2 |
|
| Relations |
| BioProject |
PRJNA453604 |
| SRA |
SRP142639 |
Less...
More...