Staphylococci secrete autoinducing peptides (AIPs) as signalling molecules to regulate population wide behavior. AIPs from non-aureus staphylococci have received attention as potential anti-virulence agents to inhibit quorum sensing (QS) and virulence gene expression in the human pathogen, Staphylococcus aureus.
To investigate AIPs, we developed an effective protocol for solid-phase synthesis of peptide thiolactones by concomitant ring closure and cleavage from the solid support. The strategy was applied for mapping the importance of the structural features in the recently isolated S. schleiferi AIP by performing alanine scan and truncation studies. This furnished some of the most potent inhibitors of accessory gene regulator (agr)-I in the human pathogen S. aureus reported to date.1
Furthermore, a limited number of AIP structures from non-aureus staphylococci have been identified as the minute amounts secreted in complex media renders it difficult. Thus, we also developed a method for the identification of AIPs by exploiting their thiolactone functionality for chemoselective trapping and enrichment of the compounds from bacterial supernatant. Standard LC-MS analysis, guided by genome sequencing data, then readily provided the AIP identities. By using this approach, we confirmed the identity of 5 known AIPs and identified the AIPs of 11 non-aureus species and we expect that the method should be extendable to AIP-expressing Gram-positive bacteria beyond the staphylococcal genus.2
1. B. H. Gless, P. Peng, K. D. Pedersen, C. H. Gotfredsen, H. Ingmer, C. A. Olsen. Structure–Activity Relationship Study Based on Auto-Inducing Peptide (AIP) from Dog Pathogen S. schleiferi. Org. Lett. 2017, 19, 5276–5279.
2. B. H. Gless, M. S. Bojer, P. Peng, M. Baldry, H. Ingmer, C. A. Olsen. Identification of Autoinducing Thiodepsipeptides from Staphylococci Enabled by Native Chemical Ligation. Nat. Chem. 2019, 11, 463–469.