Precursor-directed synthesis and biological activities of omega-alicyclic- and neo-branched tunicamycin N-acyl variants

Authors: Price, Neil; Jackson, Michael - Mike; Hartman, Trina; Bannantine, John; Naumann, Todd; Vermillion, Karl; KOCH, AARON - Cayman Chemicals; KENNEDY, PAUL - Cayman Chemicals

Submitted to: ACS Chemical Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/13/2023
Publication Date: 10/20/2023
Citation: Price, N.P.J., Jackson, M.A., Hartman, T.M., Bannantine, J.P., Naumann, T.A., Vermillion, K.E., Koch, A.A., Kennedy, P.D. 2023. Precursor-Directed Biosynthesis and Biological Testing of omega-Alicyclic- and neo-Branched Tunicamycin N-Acyl Variants. ACS Chemical Biology. 18(10):2267-2280. https://doi.org/10.1021/acschembio.3c00324.
DOI: https://doi.org/10.1021/acschembio.3c00324

Interpretive Summary: Tunicamycin (TUN) are natural products produced by Streptomyces soil bacteria. They show good antibiotic activity, but with unwanted side effects in animals. We have previously developed a modified TUN with reduced animal toxicity that has potential uses as a new antibiotic for veterinary medicine. The present research describes fifteen new TUN (called neo-TUN and OATs) that we identified by screening TUN-producing strains on different types of growth media containing fatty acid precursors.These neo-TUN/OATs were scaled up and purified in fermentation, and the chemical structures and antimicrobial properties are reported. This research greatly extends the number of tunicamycins available for antibiotic research and provides new promising antimicrobials for disease treatments in agriculture and veterinary medicine.

Technical Abstract: Tunicamycins (TUNs) are Streptomyces-derived natural products, widely used to block protein N-glycosylation in eukaryotes or cell wall biosynthesis in bacteria. Modified or synthetic TUN analogs that uncouple these activities have considerable potential as novel mode-of-action antibacterial agents. Chemically modified TUN reported previously with attenuated activity on yeast have identified eukaryotic-specific chemophores in the uridyl group and the N-acyl chain length and terminal branching pattern. A small molecule screen of fatty acid biosynthetic primers identified several novel alicyclic- and neo-branched TUN N-acyl variants, with primer incorporation at the terminal omega-acyl position. TUNs with unique 5- and 6-carbon omega-cycloalkane and omega-cycloalkene acyl chains are produced under fermentation, and in yields comparable with the native TUN. The purification, structural assignments, and the comparable antimicrobial properties of fifteen of these compounds are reported, greatly extending the structural diversity of this class of compounds for potential medicinal and agricultural applications.