Vitamin B3 Triggers Biosynthesis of Secondary Metabolite Dormancy Signals in .

TitleVitamin B3 Triggers Biosynthesis of Secondary Metabolite Dormancy Signals in .
Publication TypeJournal Article
Year of Publication2022
AuthorsCovington, BC, Seyedsayamdost, MR
JournalJ Am Chem Soc
Volume144
Issue33
Pagination14997-15001
Date Published2022 Aug 24
ISSN1520-5126
KeywordsBiological Products, Humans, Niacin, Niacinamide, Peptides, Protein Processing, Post-Translational, Ribosomes, Streptococcus suis
Abstract

<p>Human-associated streptococci have not been viewed as productive sources of natural products. Against expectation, bioinformatic searches recently revealed a large collection of diverse biosynthetic gene clusters coding for ribosomally synthesized and post-translationally modified peptides (RiPPs) in streptococcal genomes. The most abundant of these, the gene cluster, is specific to , a burdensome agricultural pathogen and zoonotic agent. Herein, we used high-throughput elicitor screening to identify both small molecule elicitors and products of the cluster. We show that the B vitamin niacin effectively elicits the cluster leading to the biosynthesis of a family of RiPP natural products, which we termed threoglucins and characterized structurally. The defining feature of threoglucins is an aliphatic ether bond giving rise to a substituted 1,3-oxazinane heterocycle in the peptide backbone. Isolation of 22 congeners of threoglucins facilitated structure activity relationship studies, demonstrating the requirement for the oxazinane substructure and a Trp-Tyr C-terminal dyad for biological activity, namely antibiotic persistence and allolysis at low and high doses, respectively. Potential therapeutic applications of threoglucins are discussed.</p>

DOI10.1021/jacs.2c05790
Alternate JournalJ Am Chem Soc
PubMed ID35969232