Planta Med 2015; 81 - PM_91
DOI: 10.1055/s-0035-1565468

Macrocylic diterpenes as modulators of Candida albicans multidrug transporters

A Mónico 1, S Nim 2, MRK Rawal 2, R Prasad 2, N Duarte 1, A Di Pietro 3, MJU Ferreira 1
  • 1Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649 – 003 Lisboa, Portugal, Av. Prof. Gama Pinto, 1649 – 003, Lisboa, Portugal
  • 2School of Life Sciences, Jawaharlal Nehru University, 110067, New Delhi, India
  • 3Equipe Labellisèe Ligue 2014, BMSSI UMR5086 CNRS and University of Lyon, IBCP, Passage du Vercors 7, 69367, Lyon, France

Fungal infections constitute a serious global health concern. The most prevalent fungal pathogens belong to the Candida genus namely Candida albicans. Candida infections have been treated mainly with azoles. However, the widespread and prolonged use of antifungals, mainly due to the use of antifungal prophylaxis in immunocompromised individuals, has resulted in the development of multidrug-resistant strains. Resistance to azole antifungal agents in Candida species is a multifactorial phenomenon, being one of the most significant mechanisms the overexpression of ABC and major facilitator superfamily (MFS) membrane transporters. Thus, a promising approach for overcoming drug resistance is the development of inhibitors of these efflux-pump proteins.

Euphorbia species are characterized by an unusual diversity of chemical constituents, including a wide range of macrocyclic diterpenes that were found to strongly modulate the transport activity of the human P-glycoprotein, considered of major importance in the MDR phenomenon in cancer. Aiming to find new reversers of antifungal resistance mediated by efflux pumps, a set of macrocyclic diterpenes of the jatrophane and lathyrane-type was evaluated for their ability to inhibit drug-efflux activity of CaCdr1 p and CaMdr1 p multidrug transporters of C. albicans overexpressed in a Saccaromyces cerevisiae strain. Their inhibitory potential was assessed through a functional assay, monitoring Nile Red (NR) accumulation by flow cytometry. A chemosensitivity assay, using the checkerboard method, was also performed with some the most active compounds in order to evaluate the type of interaction with fluconazole. In the transport assay most of the compounds were found to be dual inhibitors. Two jatrophanes were selective for CaMdr1 p or CaCdr1 p. Moreover, three jatrophanes were able to strongly sensitize yeast growth to the antifungal activity of fluconazole.

Acknowledgements: This study was funded by FCT, Portugal (PTDC/QEQ-MED/0905/2012).