{"doi":"10.1021/jacs.2c08238","title":"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.","journal":"Journal of the American Chemical Society","year":2022,"id":263677,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9607,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":698105,"name":"Amith S. Maroli","orcid":"0000-0002-0647-0316","position":1,"is_corresponding":false},{"id":613787,"name":"Aline de Lima Leite","orcid":"0000-0002-2112-1309","position":2,"is_corresponding":false},{"id":410442,"name":"Darrell D. Marshall","orcid":null,"position":3,"is_corresponding":false},{"id":921250,"name":"Boone W. Evans","orcid":null,"position":4,"is_corresponding":false},{"id":599415,"name":"Denise K. Zinniel","orcid":null,"position":5,"is_corresponding":false},{"id":780321,"name":"Patrick H. Dussault","orcid":"0000-0002-9834-1350","position":6,"is_corresponding":false},{"id":780320,"name":"Raúl G. Barletta","orcid":"0000-0002-2278-2563","position":7,"is_corresponding":false},{"id":252168,"name":"Robert Powers","orcid":"0000-0001-9948-6837","position":8,"is_corresponding":false},{"id":757158,"name":"Isin T. Sakallioglu","orcid":"0000-0001-9059-2705","position":0,"is_corresponding":true}],"reference_count":77,"raw_metadata":null,"created_at":"2026-07-19T00:26:33.413850Z","pmid":"36367461","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}