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Synthesis, bioactivity, and enzymatic modification of antibacterial thiotetromycin derivatives

TitleSynthesis, bioactivity, and enzymatic modification of antibacterial thiotetromycin derivatives
Publication TypeJournal Article
Year of Publication2019
AuthorsRothe M.L, Li J., Garibay E., Moore BS, McKinnie S.MK
JournalOrganic & Biomolecular Chemistry
Date Published2019/04
Type of ArticleArticle
ISBN Number1477-0520
Accession NumberWOS:000462795100017
Keywords5-position; analogs; antibiotics; biosynthesis; chemistry; condensing enzymes; directed evolution; fatty-acid synthesis; inhibitors; potential antimalarial; thiolactomycin

Thiotetronate-containing natural products, including thiolactomycin, thiotetromycin, and thiotetroamide, are potent, broad-spectrum antibacterial compounds that target fatty acid synthesis in bacteria. Natural modifications at the C-5 dialkyl position in this molecular series result in pronounced bioactivity differences. The C-5 acetamide-containing thiotetroamide, which is the more potent antibacterial agent in this family, is biosynthesized from the C-5 ethyl analogue thiotetromycin via a unique two-enzyme process involving the cytochrome P450-amidotransferase enzyme pair TtmP-TtmN. Herein we synthesized a focused library of 17 novel thiotetromycin derivatives differing at the 5-position alkyl substituent to investigate their biological activities and their reactivity towards the hydroxylase TtmP. Although we observed marginal anti-tuberculosis activity, select thiotetromycin analogues showed antibacterial activity against an Escherichia coli Delta tolC strain with IC50 values in a range of 1.9-36 mu g mL(-1). Additional screening efforts highlighted select thiotetronate analogues as inhibitors of the cancer-associated enzyme nicotinamide N-methyltransferase (NNMT), with a unique scaffold compared to previously identified NNMT inhibitors. In vitro assays further showed that the TtmP P450 was capable of resolving racemic substrate mixtures and had modest promiscuity to hydroxylate derivatives with variable alkyl chains; however triple oxidation to a carboxylic acid remained specific for the natural thiotetromycin substrate. The tendency of TtmP to accept a range of unnatural substrates for hydroxylation makes it an interesting target for P450 engineering towards broader applications.

Short TitleOrg. Biomol. Chem.
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