Issue 13, 2019

Synthesis, bioactivity, and enzymatic modification of antibacterial thiotetromycin derivatives

Abstract

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 ΔtolC strain with IC50 values in a range of 1.9–36 μg 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.

Graphical abstract: Synthesis, bioactivity, and enzymatic modification of antibacterial thiotetromycin derivatives

Supplementary files

Article information

Article type
Paper
Submitted
14 dic. 2018
Accepted
05 mar. 2019
First published
11 mar. 2019

Org. Biomol. Chem., 2019,17, 3416-3423

Synthesis, bioactivity, and enzymatic modification of antibacterial thiotetromycin derivatives

M. L. Rothe, J. Li, E. Garibay, B. S. Moore and S. M. K. McKinnie, Org. Biomol. Chem., 2019, 17, 3416 DOI: 10.1039/C8OB03109F

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