title: Overcoming Multidrug Resistance in Candida albicans: Macrocyclic Diterpenes from Euphorbia Species as Potent Inhibitors of Drug Efflux Pumps.
abstract: Thirteen macrocyclic diterpenes (1-13) of the jatrophane and lathyrane types, either isolated from Euphorbia species or obtained by chemical derivatization, were evaluated for their ability to inhibit the drug efflux activity of Candida albicans CaCdr1p and CaMdr1p multidrug transporters overexpressed in a Saccharomyces cerevisiae strain. Their inhibitory potential was assessed through a functional assay of Nile Red accumulation monitored by flow cytometry. A chemosensitization assay, using the checkerboard method, was also performed with the active compounds in order to evaluate their type of interaction with fluconazole.In the transport assay, most compounds were found to inhibit both transporters, most likely as non-substrates, as shown by relative resistance indices close to unity. In contrast, the jatrophanes euphopubescenol (10) and euphomelliferene A (11) were selective for CaMdr1p and CaCdr1p, respectively. Moreover, when used in combination with fluconazole, compounds 12 and 13 displayed strong synergistic interactions (FICI = 0.071) against the yeast strain overexpressing CaMdr1p, decreasing the MIC80 of the antifungal agent 13-fold. Both compounds were also able to reduce the effective concentration of this antifungal agent by 4- to 8-fold against an azole-resistant clinical isolate of C. albicans (F5).
authors.affiliation: School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Shweta
authors.initials: S
authors.lastname: Nim
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Andreia
authors.initials: A
authors.lastname: Mónico
authors.affiliation: School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Manpreet Kaur
authors.initials: MK
authors.lastname: Rawal
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Noélia
authors.initials: N
authors.lastname: Duarte
authors.affiliation: School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Prasad
authors.affiliation: BMSSI UMR5086 CNRS and University of Lyon, IBCP, Lyon, France.
authors.forename: Attilio
authors.initials: A
authors.lastname: Di Pietro
authors.affiliation: Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: Maria-José U
authors.initials: MJ
authors.lastname: Ferreira
mesh_terms: D000935:Antifungal Agents / Q000302:isolation & purification / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects*; D004224:Diterpenes / Q000302:isolation & purification / Q000494:pharmacology*; D026141:Drug Resistance, Multiple, Fungal; D028481:Euphorbia / Q000737:chemistry*; D026901:Membrane Transport Proteins / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D010936:Plant Extracts / Q000494:pharmacology*
chemical_list: D000935:Antifungal Agents; D004224:Diterpenes; D026901:Membrane Transport Proteins; D010936:Plant Extracts