Tackling <i>Pseudomonas aeruginosa</i> Virulence by Mulinane-Like Diterpenoids from <i>Azorella atacamensis</i>

• Main Authors: 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
• Format: Article
• Language: English
• Published: MDPI AG 2020-12-01
• Series: Biomolecules
• Subjects: mulinane-like diterpenoids; <i>Azorella atacamensis</i>; anti-virulence; <i>Pseudomonas aeruginosa</i>; membrane stiffness; ECFσ SigX
• Online Access: https://www.mdpi.com/2218-273X/10/12/1626

<i>Pseudomonas aeruginosa</i> 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, <i>P. aeruginosa</i> 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 <i>Azorella atacamensis</i>, a medicinal plant from the Taira Atacama community (Calama, Chile), against <i>P. aeruginosa</i>. Interestingly, <i>A. atacamensis</i> extract (<i>Aa</i>E) conferred a significant protection for human lung cells and <i>Caenorhabditis elegans</i> nematodes towards <i>P. aeruginosa</i> pathogenicity. The production of key virulence factors was decreased upon <i>Aa</i>E exposure without affecting <i>P. aeruginosa</i> growth. In addition, <i>Aa</i>E was able to decrease QS-molecules production. Furthermore, metabolite profiling of <i>Aa</i>E 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 <i>P. aeruginosa</i>. 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 <i>P. aeruginosa</i> virulence.