De novo synthesis, structural assignment and biological evaluation of pseudopaline, a metallophore produced by Pseudomonas aeruginosa

De novo synthesis, structural assignment and biological evaluation of pseudopaline, a metallophore produced by Pseudomonas aeruginosa†

Jian Zhang,‡^a Tianhu Zhao,‡^a Rongwen Yang,‡^a Ittipon Siridechakorn,^a Sanshan Wang,^a Qianqian Guo,^a Yingjie Bai,^a Hong C. Shen^b and Xiaoguang Lei

*^a

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* Corresponding authors

^a Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
E-mail: xglei@pku.edu.cn

^b Roche Innovation Center Shanghai, Roche Pharma Research & Early Development, Shanghai 201203, China

Abstract

Pseudopaline is an opine carboxylate metallophore produced by Pseudomonas aeruginosa for harvesting divalent metals. However, the structure of pseudopaline is not fully elucidated. Herein, we report the first de novo total synthesis and isolation of pseudopaline, which allows unambiguous determination and confirmation of both the absolute and the relative configuration of the natural product. The synthesis highlights an efficient and stereocontrolled route using the asymmetric Tsuji–Trost reaction as the key step. The preliminary structure–activity relationship study indicated that one pseudopaline derivative shows comparable activity to pseudopaline. Moreover, a pseudopaline-fluorescein conjugate was prepared and evaluated, which confirmed that pseudopaline could be transported in the bacteria. Since the metal acquisition by P. aeruginosa is crucial for its ability to cause diseases, our extensive structural and functional studies of pseudopaline may pave the way for developing new therapeutic strategies such as the “Trojan horse” antibiotic conjugate against P. aeruginosa.

This article is part of the themed collection: 2019 Chemical Science HOT Article Collection

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DOI: https://doi.org/10.1039/C9SC01405E
Article type: Edge Article
Submitted: 22 Mar 2019
Accepted: 27 May 2019
First published: 30 May 2019
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry

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Chem. Sci., 2019,10, 6635-6641

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