Chemistry, Department of: Faculty Series
Patrick Dussault Publications
Accessibility Remediation
If you are unable to use this item in its current form due to accessibility barriers, you may request remediation through our remediation request form.
Document Type
Article
Date of this Version
3-18-2024
Citation
J Am Chem Soc. 2022 November 23; 144(46): 21157–21173. doi:10.1021/jacs.2c08238.
Abstract
The mechanism of action (MoA) of a clickable fatty acid analogue 8-(2-Cyclobuten-1-yl)octanoic acid (DA-CB) has been investigated for the first time. Proteomics, metabolomics, and lipidomics were combined with a network analysis to investigate the MoA of DA-CB against Mycobacterium smegmatis (Msm). The metabolomics results showed that DA-CB has a general MoA related to that of ethionamide, a mycolic acid inhibitor that targets enoyl-ACP reductase (InhA), but DA-CB likely inhibits a step downstream from InhA. Our combined multi-omics approach showed that DA-CB appears to disrupt the pathway leading to the biosynthesis of mycolic acids, an essential mycobacterial fatty acid for both Msm and Mycobacterium tuberculosis (Mtb). DA-CB decreased keto-meromycolic acid biosynthesis. This intermediate is essential in the formation of mature mycolic acid, which is a key component of the mycobacterial cell wall in a process that is catalyzed by the essential polyketide synthase Pks13 and the associated ligase FadD32. The multi-omics analysis revealed further collateral alterations in bacterial metabolism including the overproduction of shorter carbon-chain hydroxy- and branched chain fatty acids, alterations in pyrimidine metabolism, and a predominately down-regulation of proteins involved in fatty acid biosynthesis. Overall, the results with DA-CB suggest the exploration of this and related compounds as a new class of tuberculosis therapeutics. Furthermore, the clickable nature of
Comments
HHS Public Access.