Azetidine-Containing Alkaloids Produced by a Quorum-Sensing Regulated Nonribosomal Peptide Synthetase Pathway in Pseudomonas aeruginosa

Zhilai Hong; Arnaud Bolard; Caroline Giraud; Sébastien Prevost; Grégory Genta-Jouve; Christiane Deregnaucourt; Susanne Häussler; Katy Jeannot; Yanyan Li

Azetidine-Containing Alkaloids Produced by a Quorum-Sensing Regulated Nonribosomal Peptide Synthetase Pathway in Pseudomonas aeruginosa

Zhilai Hong ¹ Arnaud Bolard ² Caroline Giraud ³ Sébastien Prevost ⁴ Grégory Genta-Jouve ^{5, 6, 7} Christiane Deregnaucourt ¹ Susanne Häussler ^{8, 9} Katy Jeannot ^{2, *} Yanyan Li ^{1, *}

* Corresponding author

1 MCAM - Molécules de Communication et Adaptation des Micro-organismes (MCAM)

2 CNR - Centre National de Référence de la Résistance aux Antibiotiques

3 U2RM - Unité de Recherche Risques Microbiens

4 DCSO - Laboratoire de synthèse organique

5 UMR 8638 - Equipe C-TAC

COMETE - UMR 8638 - Chimie Organique, Médicinale et Extractive et Toxicologie Expérimentale

6 UPD5 Pharmacie - Université Paris Descartes - Faculté de Pharmacie de Paris

7 USPC - Université Sorbonne Paris Cité

8 TWINCORE - Centre for Experimental and Clinical Infection Research

9 HZI - Helmholtz Centre for Infection Research

Abstract : Pseudomonas aeruginosa displays an impressive metabolic versatility, which ensures its survival in diverse environments. Reported herein is the identification of rare azetidine-containing alkaloids from P. aeruginosa PAO1, termed azetidomonamides, which are derived from a conserved, quorum-sensing regulated nonribosomal peptide synthetase (NRPS) pathway. Biosynthesis of the azetidine motif has been elucidated by gene inactivation, feeding experiments, and biochemical characterization in vitro, which involves a new S-adenosylmethionine-dependent enzyme to produce azetidine 2-carboxylic acid as an unusual building block of NRPS. The mutants of P. aeruginosa unable to produce azetidomonamides had an advantage in growth at high cell density in vitro and displayed rapid virulence in Galleria mellonella model, inferring functional roles of azetidomonamides in the host adaptation. This work opens the avenue to study the biological functions of azetidomonamides and related compounds in pathogenic and environmental bacteria.

Keywords : natural products quorum sensing enzymes alkaloids biosynthesis

Document type :

Journal articles

Domain :

Chemical Sciences / Organic chemistry

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https://hal-polytechnique.archives-ouvertes.fr/hal-02096769
Contributor : Aurélien Arnoux <>
Submitted on : Thursday, April 11, 2019 - 3:30:39 PM
Last modification on : Friday, May 10, 2019 - 10:00:07 AM

Azetidine-Containing Alkaloids Produced by a Quorum-Sensing Regulated Nonribosomal Peptide Synthetase Pathway in Pseudomonas aeruginosa

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Azetidine-Containing Alkaloids Produced by a Quorum-Sensing Regulated Nonribosomal Peptide Synthetase Pathway in Pseudomonas aeruginosa

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