1. Generation of Fluorinated Amychelin Siderophores against Pseudomonas aeruginosa Infections by a Combination of Genome Mining and Mutasynthesis
- Author
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Lixin Zhang, Shen Yu, Huanqin Dai, Yu Zhao, Xueting Liu, Zengchun Ji, Fuhang Song, Xiangyin Chen, Feng Xie, Biao Ren, Jie Zhang, Hongwei Liu, Lan Jiang, Gil Alterovitz, Frederick M. Ausubel, Pei Huang, Qi Zhang, Qiushui Wang, and Shengwang Dai
- Subjects
Siderophore ,Halogenation ,Host–pathogen interaction ,Clinical Biochemistry ,Drug Evaluation, Preclinical ,Ceftazidime ,Siderophores ,Computational biology ,medicine.disease_cause ,01 natural sciences ,Biochemistry ,Actinobacteria ,Drug Discovery ,medicine ,Animals ,Data Mining ,Caenorhabditis elegans ,Molecular Biology ,Gene ,Pharmacology ,biology ,010405 organic chemistry ,Drug discovery ,Pseudomonas aeruginosa ,Genomics ,Meropenem ,biology.organism_classification ,0104 chemical sciences ,Anti-Bacterial Agents ,Molecular Medicine ,medicine.drug - Abstract
Summary 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 comprising Caenorhabditis elegans and Pseudomonas 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 an Amycolatopsis methanolica strain 239T chorismate to salicylate a biosynthetic subpathway for mutasynthesis. This allowed us to generate the fluorinated amychelin, fluoroamychelin I, which rescued C. elegans from P. aeruginosa-mediated killing with an EC50 value 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.
- Published
- 2020