The human microbiome-derived antibiotic lugdunin self-regulates its biosynthesis in a quorum-sensing like fashion

Many human microbiome members inhibit bacterial competitors by production of antimicrobial compounds whose expression needs to be tightly controlled to balance costs and benefits of compound biosynthesis. The nasal commensal Staphylococcus lugdunensis outcompetes Staphylococcus aureus using the antimicrobial lugdunin. The lugdunin biosynthetic gene cluster (BGC) encodes two potential regulators whose role has remained unknown. Deletion of the regulator genes lugR or lugJ led to increased lugdunin production and/or immunity. Whereas LugR was found to repress transcription of the biosynthetic lugRABCTDZ operon, LugJ repressed the lugIEFGH export and immunity genes. Both regulators bound to different inverted repeats in the controlled promoter regions. Notably, both repressors were released from cognate promoters to allow transcription upon addition of exogenous lugdunin. Even minor structural changes disabled lugdunin derivatives to induce expression of its BGC, which is consistent with inferior binding to the predicted LugR and LugJ binding pockets. Thus, lugdunin controls its own biosynthesis in a quorum-sensing-like fashion probably to avoid futile production.