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bioRxiv · 10.1101/2023.06.21.545946

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

Carson, D. V.·Zhang, Y.·So, L.·Cheung-Lee, W. L.·Cartagena, A. J.·Darst, S. A.·Link, A. J.
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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.

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Carson, D. V., Zhang, Y., So, L., Cheung-Lee, W. L., Cartagena, A. J., Darst, S. A., Link, A. J.. 2023-06-22. Discovery, Characterization, and Bioactivity of the Achromonodins: Lasso Peptides Encoded by Achromobacter. https://doi.org/10.1101/2023.06.21.545946

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