Tackling Pseudomonas aeruginosa Virulence by Mulinane-Like Diterpenoids from Azorella atacamensis

Onyedikachi Cecil Azuama, Sergio Ortiz, Luis Quirós-Guerrero, Emeline Bouffartigues, Damien Tortuel, Olivier Maillot, Marc Feuilloley, Pierre Cornelis, Olivier Lesouhaitier, Raphaël Grougnet, Sabrina Boutefnouchet, Jean-Luc Wolfender, Sylvie Chevalier, Ali Tahrioui

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Abstract

Pseudomonas aeruginosa is an important multidrug-resistant human pathogen by dint of its high intrinsic, acquired, and adaptive resistance mechanisms, causing great concern for immune-compromised individuals and public health. Additionally, P. aeruginosa resilience lies in the production of a myriad of virulence factors, which are known to be tightly regulated by the quorum sensing (QS) system. Anti-virulence therapy has been adopted as an innovative alternative approach to circumvent bacterial antibiotic resistance. Since plants are known repositories of natural phytochemicals, herein, we explored the anti-virulence potential of Azorella atacamensis, a medicinal plant from the Taira Atacama community (Calama, Chile), against P. aeruginosa. Interestingly, A. atacamensis extract (AaE) conferred a significant protection for human lung cells and Caenorhabditis elegans nematodes towards P. aeruginosa pathogenicity. The production of key virulence factors was decreased upon AaE exposure without affecting P. aeruginosa growth. In addition, AaE was able to decrease QS-molecules production. Furthermore, metabolite profiling of AaE and its derived fractions achieved by combination of a molecular network and in silico annotation allowed the putative identification of fourteen diterpenoids bearing a mulinane-like skeleton. Remarkably, this unique interesting group of diterpenoids seems to be responsible for the interference with virulence factors as well as on the perturbation of membrane homeostasis of P. aeruginosa. Hence, there was a significant increase in membrane stiffness, which appears to be modulated by the cell wall stress response ECFσ SigX, an extracytoplasmic function sigma factor involved in membrane homeostasis as well as P. aeruginosa virulence.

Original languageEnglish
Article number1626
Pages (from-to)1-25
Number of pages25
JournalBiomolecules
Volume10
Issue number12
DOIs
Publication statusPublished - 2 Dec 2020

Bibliographical note

Funding Information:
Funding: The LMSM is supported by the Région Normandie (France), Evreux Portes de Normandie (France) and European FEDER funds. PNAS is a partner of the European Union’s H2020-MSCA-RISE-2015 EXANDAS (Exploitation of aromatic plants’ by-products for the development of novel cosmeceuticals and food supplements, Grant Agreement 691247). O.C.A. is supported by a postgraduate fellowship from Campus France and FUNAI (Nigeria). S.O. is supported by a CONICYT’s scholarship (Comisión Nacional de Investigación Científica y Tecnológica from Chile). L.Q-G is supported by a scholarship (N◦ 214171–025) Ministerio de Ciencia, Tecnología y Telecomunicaciones, MICITT, from Costa Rica. The APC was funded by University of Rouen Normandy.

Funding Information:
Acknowledgments: We gratefully acknowledge Paul Williams (Centre for Biomolecular Sciences, University of Nottingham) for providing PAO1 ∆pqsA CTX-pqsA::lux biosensor strain. The Caenorhabditis elegans wild-type Bristol strain N2 was provided by the Caenorhabditis Genetics Center (CGC), which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). We wish to thank Magalie Barreau for technical assistance.

Funding Information:
The LMSM is supported by the Région Normandie (France), Evreux Portes de Normandie (France) and European FEDER funds. PNAS is a partner of the European Union’s H2020-MSCA-RISE-2015 EXANDAS (Exploitation of aromatic plants’ by-products for the development of novel cosmeceuticals and food supplements, Grant Agreement 691247). O.C.A. is supported by a postgraduate fellowship from Campus France and FUNAI (Nigeria). S.O. is supported by a CONICYT’s scholarship (Comisión Nacional de Investigación Científica y Tecnológica from Chile). L.Q-G is supported by a scholarship (N◦ 214171–025) Ministerio de Ciencia, Tecnología y Telecomunicaciones, MICITT, from Costa Rica. The APC was funded by University of Rouen Normandy.

Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

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