Vitamin B3 Triggers Biosynthesis of Secondary Metabolite Dormancy Signals in Streptococcus suis .
Brett C CovingtonMohammad R SeyedsayamdostPublished in: Journal of the American Chemical Society (2022)
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 tqq gene cluster, is specific to Streptococcus suis , a burdensome agricultural pathogen and zoonotic agent. Herein, we used high-throughput elicitor screening to identify both small molecule elicitors and products of the tqq cluster. We show that the B 3 vitamin niacin effectively elicits the tqq 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.
Keyphrases
- small molecule
- candida albicans
- high throughput
- structure activity relationship
- biofilm formation
- copy number
- genome wide
- endothelial cells
- single cell
- machine learning
- heavy metals
- cell wall
- genome wide identification
- molecular docking
- ionic liquid
- staphylococcus aureus
- protein protein
- pluripotent stem cells
- amino acid