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Multi-omics Investigation into the Mechanism of Action of an Anti-tubercular Fatty Acid Analogue.

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 (ETH), 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 fatty acids and branched chain fatty acids, alterations in pyrimidine metabolism, and a predominate downregulation 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 (TB) therapeutics. Furthermore, the clickable nature of DA-CB may be leveraged to trace the cellular fate of the modified fatty acid or any derived metabolite or biosynthetic intermediate.

SUBMITTER: Sakallioglu IT

PROVIDER: S-EPMC10948109 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Multi-omics Investigation into the Mechanism of Action of an Anti-tubercular Fatty Acid Analogue.

Sakallioglu Isin T IT Maroli Amith S AS De Lima Leite Aline A Marshall Darrell D DD Evans Boone W BW Zinniel Denise K DK Dussault Patrick H PH Barletta Raúl G RG Powers Robert R

Journal of the American Chemical Society 20221111 46

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 <i>Mycobacterium smegmatis</i> (<i>Msm</i>). The metabolomics results showed that DA-CB has a general MoA related to that of ethionamide (ETH), a mycolic acid inhibitor that targets enoyl-ACP reductase (InhA), but DA-CB likely inhi ...[more]

PMID: 36367461

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Multi-omics Investigation into the Mechanism of Action of an Anti-tubercular Fatty Acid Analogue.

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Multi-omics Investigation into the Mechanism of Action of an Anti-tubercular Fatty Acid Analogue.

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