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Werman, Joshua M. ; Chen, Yu-Ching ; Yuan, Tianao , et al. ACS Infect. Dis.,2023,9(10):1993-2004. DOI: 10.1021/acsinfecdis.3c00296 PubMed ID: 37774412
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Abstract: By illuminating key 6-azasteroid-protein interactions in both Mycobacterium tuberculosis (Mtb) and the closely related model organism Mycobacterium marinum (Mm), we sought to improve the antimycobacterial potency of 6-azasteroids and further our understanding of the mechanisms responsible for their potentiation of the antituberculosis drug bedaquiline. We selected a newly developed 6-azasteroid analog and an analog reported previously (ACS Infect. Dis.2019, 5 (7), 1239-1251) to study their phenotypic effects on Mtb and Mm, both alone and in combination with bedaquiline. The 6-azasteroid analog, 17β-[N-(4-trifluoromethoxy-diphenylmethyl)carbamoyl]-6-propyl-azaandrostan-3-one, robustly potentiated bedaquiline-mediated antimycobacterial activity, with a nearly 8-fold reduction in Mm bedaquiline minimal inhibitory concentration (85 nM alone vs. 11 nM with 20 μM 6-azasteroid). This analog displayed minimal inhibitory activity against recombinant mycobacterial 3β-hydroxysteroid dehydrogenase, a previously identified target of several 6-azasteroids. Dose-dependent potentiation of bedaquiline by this analog reduced mycobacterial intracellular ATP levels and impeded the ability of Mtb to neutralize exogenous oxidative stress in culture. We developed two 6-azasteroid photoaffinity probes to investigate azasteroid-protein interactions in Mm whole cells. Using bottom-up mass spectrometric profiling of the cross-linked proteins, we identified eight potential Mm/Mtb protein targets for 6-azasteroids. The nature of these potential targets indicates that proteins related to oxidative stress resistance play a key role in the BDQ-potentiating activity of azasteroids and highlights the potential impact of inhibition of these targets on the generation of drug sensitivity.
Keywords: photoaffinity label ; click chemistry ; synergy ; potentiator ; oxidative stress ; inhibitor
Purchased from AmBeed: 2049109-24-0 ; 611-98-3
CAS No. : | 611-98-3 | MDL No. : | MFCD00038138 |
Formula : | C13H12N2O | Boiling Point : | No data available |
Linear Structure Formula : | H2NC6H4COC6H4NH2 | InChI Key : | ZLSMCQSGRWNEGX-UHFFFAOYSA-N |
M.W : | 212.25 | Pubchem ID : | 69149 |
Synonyms : |
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Chemical Name : | Bis(4-aminophenyl)methanone |
Signal Word: | Warning | Class: | |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | |
Hazard Statements: | H315-H319-H335 | Packing Group: | |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.