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

Author:

Carson Drew V.ORCID,Zhang Yi,So LarryORCID,Cheung-Lee Wai LingORCID,Cartagena Alexis JaramilloORCID,Darst Seth A.ORCID,Link A. JamesORCID

Abstract

AbstractThrough genome mining efforts, we discovered two lasso peptide biosynthetic gene clusters (BGCs) within two different species ofAchromobacter, a genus that contains pathogenic organisms that can infect patients with cystic fibrosis. Using gene-refactored BGCs inE. 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 RNAPin vitroand has potent but narrow-spectrum activity towardsAchromobacter pulmonis, another isolate from the sputum of a cystic fibrosis patient. Our efforts expand the repertoire of antimicrobial lasso peptides and provide insights into howAchromobacterisolates from certain ecological niches may interact with each other.

Publisher

Cold Spring Harbor Laboratory

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