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Abstract Lasso peptides are an increasingly relevant class of peptide natural products with diverse biological activities, intriguing physical properties, and unique chemical structures. Most characterized lasso peptides have been from Actinobacteria and Proteobacteria, despite bioinformatic analyses suggesting that other bacterial taxa, particularly those from Firmicutes, are rich in biosynthetic gene clusters (BGCs) encoding lasso peptides. Herein, we report the bioinformatic identification of a lasso peptide BGC fromPaenibacillus taiwanensisDSM18679 which we termedpats. We used a bioinformatics‐guided isolation approach and high‐resolution tandem mass spectrometry (HRMS/MS) to isolate and subsequently characterize a new lasso peptide produced from thepatsBGC, which we named trilenodin, after the tri‐isoleucine motif present in its primary sequence. This tri‐isoleucine motif is unique among currently characterized lasso peptides. We confirmed the connection between thepatsBGC and trilenodin production by establishing the firstBacillus subtilis168‐based heterologous expression system for expressing Firmicutes lasso peptides. We finally determined that trilenodin exhibits potent antimicrobial activity againstB. subtilisandKlebsiella pneumoniae, making trilenodin the first characterized biologically active lasso peptide from Firmicutes. Collectively, we demonstrate that bacteria from Firmicutes can serve as high‐potential sources of chemically and biologically diverse lasso peptides.