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bioRxiv · 10.1101/2022.09.12.507720

Paecilomycone inhibits quorum sensing in Gram-negative bacteria

Beenker, W. A.·Hoeksma, J.·Marie Bannier-Helaouët, M.·Clevers, H.·den Hertog, J.
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Abstract

Pseudomonas aeruginosa is an opportunistic pathogen that causes major healthcare concerns due to its virulence and high intrinsic resistance to antimicrobial agents. Therefore, new treatments are highly needed. An interesting approach is to target quorum sensing (QS). QS regulates the production of a wide variety of virulence factors and biofilm formation in P. aeruginosa. This study describes the identification of paecilomycone as inhibitor of QS in both C. violaceum and P. aeruginosa. Paecilomycone strongly inhibited the production of virulence factors, including various phenazines, and biofilm formation. In search of the working mechanism, we found that paecilomycone inhibited the production of 4-hydroxy-2-heptylquinoline (HHQ) and 3,4- dihydroxy-2-heptylquinoline (PQS), but not 2-aminoacetophenone (2-AA). We suggest that paecilomycone affects QS in P. aeruginosa by targeting the PqsBC complex and alternative targets, or alters processes that influence the enzymatic activity of the PqsBC complex. The toxicity of paecilomycone towards eukaryotic cells and organisms was low, making it an interesting lead for further clinical research. ImportanceAntibiotics are becoming less effective against bacterial infections due to the evolution of resistance among bacteria. Pseudomonas aeruginosa is a Gram-negative pathogen that causes major healthcare concerns and is difficult to treat due to its high intrinsic resistance to antimicrobial agents. Therefore, new targets are needed and an interesting approach is to target quorum sensing (QS). QS is the communication system in bacteria that regulates multiple pathways including the production of virulence factors and biofilm formation, which leads to high toxicity in the host and low sensitivity to antibiotics, respectively. We found a compound, named paecilomycone, which inhibited biofilm formation and the production of various virulence factors in P. aeruginosa. The toxicity of paecilomycone towards eukaryotic cells and organisms was low, making it an interesting lead for further clinical research.

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Beenker, W. A., Hoeksma, J., Marie Bannier-Helaouët, M., Clevers, H., den Hertog, J.. 2022-09-14. Paecilomycone inhibits quorum sensing in Gram-negative bacteria. https://doi.org/10.1101/2022.09.12.507720

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