Abstract
Aim: Caffeic acid (3,4-dihydroxycinnamic acid) phenethyl ester (CAPE), the major constituent of propolis, is able to increase the survival of the nematode Caenorhabditis elegans after infection with the fungal pathogen Candida albicans. Results: CAPE increases the expression of several antimicrobial proteins involved in the immune response to C. albicans. Structural derivatives of CAPE were synthesized to identify structure–activity relationships and decrease metabolic liability, ultimately leading to a compound that has similar efficacy, but increased in vivo stability. The CED-10(Rac-1)/PAK1 pathway was essential for immunomodulation by CAPE and was a critical component involved in the immune response to fungal pathogens. Conclusion:Caenorhabditis elegans is an efficient heterologous host to evaluate immunomodulatory compounds and identify components of the pathway(s) involved in the mode of action of compounds.
Acknowledgements
The authors would like to thank R Pukkila-Worley for guidance and oligos regarding the expression studies. The authors would like to thank S Johnston for analytical chemistry support and Sai Life Sciences for their analog synthesis support.
Financial & competing interests disclosure
This research was made possible by NIH funding from the National Institute of Allergy and Infectious Diseases P01 AI083214 to E Mylonakis and National Cancer Institute RC2 CA148399 to AN Koehler, and a grant from the Rhode Island Medical Foundation to JJ Coleman. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.