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| Status |
Public on Jul 02, 2021 |
| Title |
AC2P20 selectively kills M. tuberculosis at acidic pH by depleting free thiols |
| Organism |
Mycobacterium tuberculosis CDC1551 |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
In this study, AC2P20 was prioritized for continued study to test the hypothesis that it was targeting Mtb pathways associated with pH-driven adaptation. RNAseq transcriptional profiling studies showed AC2P20 modulates expression of genes associated with redox-homeostasis. Gene enrichment analysis revealed that the AC2P20 transcriptional profile had significant overlap with a previously characterized pH-selective inhibitor, AC2P36. Like AC2P36, we show that AC2P20 kills Mtb by selectively depleting free thiols at acidic pH. Mass spectrometry studies show the formation of a disulfide bond between AC2P20 and reduced glutathione, supporting a mechanism where AC2P20 is able to deplete intracellular thiols and dysregulate redox homeostasis.
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| Overall design |
Examination of M. tuberculosis treated with 20 uM AC2P20 for 24h hours at pH 5.7 as compared to a DSMO control
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| |
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| Contributor(s) |
Dechow SJ, Coulson GB, Wilson MW, Larsen SD, Abramovitch RB |
| Citation(s) |
34168865 |
| |
| Submission date |
Jun 05, 2020 |
| Last update date |
Jul 02, 2021 |
| Contact name |
Robert B. Abramovitch |
| Organization name |
Michigan State University
|
| Department |
Microbiology and Molecular Genetics
|
| Street address |
567 Wilson Road
|
| City |
East Lansing |
| State/province |
MI |
| ZIP/Postal code |
48824 |
| Country |
USA |
| |
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| Platforms (1) |
| GPL20114 |
Illumina HiSeq 2500 (Mycobacterium tuberculosis CDC1551) |
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| Samples (4)
|
| GSM4592681 |
DMSO_1: WT treated with DMSO, pH 5.7 rep 1 |
| GSM4592682 |
DMSO_2: WT treated with DMSO, pH 5.7 rep 2 |
| GSM4592683 |
AC2P20_1: WT treated with AC2P20, pH 5.7 rep 1 |
| GSM4592684 |
AC2P20_2: WT treated with AC2P20, pH 5.7 rep 2 |
|
| Relations |
| BioProject |
PRJNA637583 |
| SRA |
SRP266131 |
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