title: The quorum-sensing molecule farnesol is a modulator of drug efflux mediated by ABC multidrug transporters and synergizes with drugs in Candida albicans.
abstract: Overexpression of the CaCDR1-encoded multidrug efflux pump protein CaCdr1p (Candida drug resistance protein 1), belonging to the ATP binding cassette (ABC) superfamily of transporters, is one of the most prominent contributors of multidrug resistance (MDR) in Candida albicans. Thus, blocking or modulating the function of the drug efflux pumps represents an attractive approach in combating MDR. In the present study, we provide first evidence that the quorum-sensing molecule farnesol (FAR) is a specific modulator of efflux mediated by ABC multidrug transporters, such as CaCdr1p and CaCdr2p of C. albicans and ScPdr5p of Saccharomyces cerevisiae. Interestingly, FAR did not modulate the efflux mediated by the multidrug extrusion pump protein CaMdr1p, belonging to the major facilitator superfamily (MFS). Kinetic data revealed that FAR competitively inhibited rhodamine 6G efflux in CaCdr1p-overexpressing cells, with a simultaneous increase in an apparent K(m) without affecting the V(max) values and the ATPase activity. We also observed that when used in combination, FAR at a nontoxic concentration synergized with the drugs at their respective nonlethal concentrations, as was evident from their <0.5 fractional inhibitory concentration index (FICI) values and from the drop of 14- to 64-fold in the MIC(80) values in the wild-type strain and in azole-resistant clinical isolates of C. albicans. Our biochemical experiments revealed that the synergistic interaction of FAR with the drugs led to reactive oxygen species accumulation, which triggered early apoptosis, and that both could be partly reversed by the addition of an antioxidant. Collectively, FAR modulates drug extrusion mediated exclusively by ABC proteins and is synergistic to fluconazole (FLC), ketoconazole (KTC), miconazole (MCZ), and amphotericin (AMB).
authors.affiliation: Membrane Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi 110067, India.
authors.forename: Monika
authors.initials: M
authors.lastname: Sharma
authors.forename: Rajendra
authors.initials: R
authors.lastname: Prasad
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000666:Amphotericin B / Q000494:pharmacology; D000935:Antifungal Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis; D001693:Biological Transport, Active / Q000187:drug effects; D002176:Candida albicans / Q000187:drug effects* / Q000378:metabolism; D026141:Drug Resistance, Multiple, Fungal; D004357:Drug Synergism; D005204:Farnesol / Q000378:metabolism / Q000494:pharmacology*; D015725:Fluconazole / Q000494:pharmacology; D005656:Fungal Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007654:Ketoconazole / Q000494:pharmacology; D007700:Kinetics; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008825:Miconazole / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D053038:Quorum Sensing; D017382:Reactive Oxygen Species / Q000378:metabolism; D012235:Rhodamines / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D000935:Antifungal Agents; C094693:CDR1 protein, Candida albicans; D005656:Fungal Proteins; D026901:Membrane Transport Proteins; D017382:Reactive Oxygen Species; D012235:Rhodamines; C026188:rhodamine 6G; D005204:Farnesol; D008825:Miconazole; D000666:Amphotericin B; D015725:Fluconazole; D007654:Ketoconazole