Discovery, Characterization, and Bioactivity of the Achromonodins: Lasso Peptides Encoded by Achromobacter

Abstract

Through genome mining efforts, we discovered two lasso peptide biosynthetic gene clusters (BGCs) within two different species of Achromobacter, a genus that contains pathogenic organisms that can infect patients with cystic fibrosis. Using gene-refactored BGCs in E. coli, we heterologously expressed two lasso peptides, which we named achromonodin-1 and achromonodin-2. Achromonodin-1 is naturally encoded by certain isolates from the sputum of patients with cystic fibrosis. We solve the NMR structure of achromonodin-1, demonstrating that it is a threaded lasso peptide with a large loop and short tail structure, reminiscent of previously characterized lasso peptides that inhibit RNA polymerase (RNAP). We then show that achromonodin-1 inhibits RNAP in vitro and has potent but narrow-spectrum activity towards Achromobacter pulmonis, another isolate from the sputum of a cystic fibrosis patient. Our efforts expand the repertoire of antimicrobial lasso peptides and provide insights into how Achromobacter isolates from certain ecological niches may interact with each other.