Generation of Fluorinated Amychelin Siderophores against Pseudomonas aeruginosa Infections by a Combination of Genome Mining and Mutasynthesis

摘要

Pioneering microbial genomic surveys have revealed numerous untapped biosynthetic gene clusters, unveiling the great potential of new natural products. Here, using a combination of genome mining, mutasynthesis, and activity screening in an infection model comprisingCaenorhabditis elegansandPseudomonas aeruginosa, we identified candidate virulence-blocking amychelin siderophore compounds from actinomycetes. Subsequently, we developed unreported analogs of these virulence-blocking siderophores with improved potency by exploiting anAmycolatopsis methanolicastrain 239Tchorismate to salicylate a biosynthetic subpathway for mutasynthesis. This allowed us to generate the fluorinated amychelin, fluoroamychelin I, which rescuedC.elegansfromP.aeruginosa-mediated killing with an EC50value of 1.4?μM, outperforming traditional antibiotics including ceftazidime and meropenem. In general, this paper describes an efficient platform for the identification and production of classes of anti-microbial compounds with potential unique modes of action.