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Planta Med 2016; 82(13): 1180-1185
DOI: 10.1055/s-0042-106169
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Overcoming Multidrug Resistance in Candida albicans: Macrocyclic Diterpenes from Euphorbia Species as Potent Inhibitors of Drug Efflux Pumps

Shweta Nim
1   School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
,
Andreia Mónico
2   Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal
,
Manpreet Kaur Rawal
1   School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
,
Noélia Duarte
2   Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal
,
Rajendra Prasad
1   School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
3   Amity Institute of Integrative Sciences and Health, AMITY University, Education Valley, Gurgaon, India
,
Attilio Di Pietro   *
4   BMSSI UMR5086 CNRS and University of Lyon, IBCP, Lyon, France
,
Maria-José U. Ferreira   *
2   Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisboa, Portugal
› Author Affiliations
Further Information

Publication History

received 09 February 2016
revised 23 March 2016

accepted 03 April 2016

Publication Date:
04 May 2016 (online)

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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).

Key words

Euphorbiaceae - macrocyclic diterpenes - multidrug resistance - drug-efflux pumps - CaCdr1p and CaMdr1p transporters - inhibitors - Candida albicans

* Coauthors.


Supporting Information

 

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