The Quorum-Sensing Molecule Farnesol Is a Modulator of Drug Efflux Mediated by ABC Multidrug Transporters and Synergizes with Drugs in Candida albicans

Sharma, Monika; Prasad, Rajendra

doi:10.1128/aac.00344-11

Cited by 108 publications

(89 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The efflux of R6G was measured using a previously described protocol (24,33). Competition experiments with ITC and farnesol were determined according to previously described protocols (22,34). The accumulation of Nile Red by exponential phase yeast cells was determined by modification of a previously described method (35).…”

Section: Methodsmentioning

confidence: 99%

Insight into Pleiotropic Drug Resistance ATP-binding Cassette Pump Drug Transport through Mutagenesis of Cdr1p Transmembrane Domains*

Rawal¹,

Khan

Kapoor³

et al. 2013

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background:The Candida albicans efflux pump Cdr1p causes clinically significant antifungal resistance. Results: Biochemical mapping of Cdr1p transmembrane domain mutants reveals residues affecting drug transport. Conclusion: Functional characterization and homology modeling provide insight into the drug binding cavity and substrate promiscuity of Cdr1p. Significance: A platform is provided for systematic Cdr1p structure/function analysis and the rational design of transport modulators/inhibitors.

show abstract

Section: Methodsmentioning

confidence: 99%

Insight into Pleiotropic Drug Resistance ATP-binding Cassette Pump Drug Transport through Mutagenesis of Cdr1p Transmembrane Domains*

Rawal¹,

Khan

Kapoor³

et al. 2013

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…We have shown earlier that a disulfiram drug (Antabuse) inhibits the oligomycin-sensitive ATPase activity of Cdr1p (57). In addition, the polyphenol curcumin and the quorum-sensing molecule farnesol act as modulators of Cdr1p (58,59). Notably, disulfiram, curcumin, and farnesol also potentiate antifungal activity and thus display synergy with certain antifungals.…”

Section: Modulators/inhibitors Of Cdr1pmentioning

confidence: 98%

The ABCs of Candida albicans Multidrug Transporter Cdr1

et al. 2015

Self Cite

View full text Add to dashboard Cite

bIn the light of multidrug resistance (MDR) among pathogenic microbes and cancer cells, membrane transporters have gained profound clinical significance. Chemotherapeutic failure, by far, has been attributed mainly to the robust and diverse array of these proteins, which are omnipresent in every stratum of the living world. Candida albicans, one of the major fungal pathogens affecting immunocompromised patients, also develops MDR during the course of chemotherapy. The pivotal membrane transporters that C. albicans has exploited as one of the strategies to develop MDR belongs to either the ATP binding cassette (ABC) or the major facilitator superfamily (MFS) class of proteins. The ABC transporter Candida drug resistance 1 protein (Cdr1p) is a major player among these transporters that enables the pathogen to outplay the battery of antifungals encountered by it. The promiscuous Cdr1 protein fulfills the quintessential need of a model to study molecular mechanisms of multidrug transporter regulation and structure-function analyses of asymmetric ABC transporters. In this review, we cover the highlights of two decades of research on Cdr1p that has provided a platform to study its structure-function relationships and regulatory circuitry for a better understanding of MDR not only in yeast but also in other organisms.

show abstract

“…Encouraged by these findings, we (34,35,36,38, and 40 g/ml, respectively). The data represent the means Ϯ the standard errors from three independent experiments (*, P Ͻ 0.05).…”

Section: To 6)mentioning

confidence: 60%

“…Inhibition of the pump ATPase activity is, however, not the only mechanism blocking CaCdr1p-mediated fluconazole transport. There are molecules that reverse fluconazole resistance mediated by CaCdr1p without affecting its pump ATPase activity (e.g., chalcone derivatives [18], farnesol [36], and curcumin [20]). Although we cannot say how these compounds inhibit C. albicans Cdr1p and Mdr1p, it is certain that some of the organotellurium compounds 1 to 5 could chemosensitize C. albicans-resistant isolates to fluconazole.…”

Section: Discussionmentioning

confidence: 99%

Synthetic Organotellurium Compounds Sensitize Drug-Resistant Candida albicans Clinical Isolates to Fluconazole

Sá

Toledo

Gonçalves

et al. 2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Invasive Candida albicans infections are a serious health threat for immunocompromised individuals. Fluconazole is most commonly used to treat these infections, but resistance due to the overexpression of multidrug efflux pumps is of grave concern. This study evaluated the ability of five synthetic organotellurium compounds to reverse the fluconazole resistance of C. albicans clinical isolates. Compounds 1 to 4, at Ͻ10 g/ml, ameliorated the fluconazole resistance of Saccharomyces cerevisiae strains overexpressing the major C. albicans multidrug efflux pumps Cdr1p and Mdr1p, whereas compound 5 only sensitized Mdr1p-overexpressing strains to fluconazole. Compounds 1 to 4 also inhibited efflux of the fluorescent substrate rhodamine 6G and the ATPase activity of Cdr1p, whereas all five of compounds 1 to 5 inhibited Nile red efflux by Mdr1p. Interestingly, all five compounds demonstrated synergy with fluconazole against efflux pump-overexpressing fluconazoleresistant C. albicans clinical isolates, isolate 95-142 overexpressing CDR1 and CDR2, isolate 96-25 overexpressing MDR1 and ERG11, and isolate 12-99 overexpressing CDR1, CDR2, MDR1, and ERG11. Overall, organotellurium compounds 1 and 2 were the most promising fluconazole chemosensitizers of fluconazole-resistant C. albicans isolates. Our data suggest that these novel organotellurium compounds inhibit pump efflux by two very important and distinct families of fungal multidrug efflux pumps: the ATP-binding cassette transporter Cdr1p and the major facilitator superfamily transporter Mdr1p.

show abstract

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

Cited by 108 publications

References 34 publications

Insight into Pleiotropic Drug Resistance ATP-binding Cassette Pump Drug Transport through Mutagenesis of Cdr1p Transmembrane Domains*

Insight into Pleiotropic Drug Resistance ATP-binding Cassette Pump Drug Transport through Mutagenesis of Cdr1p Transmembrane Domains*

The ABCs of Candida albicans Multidrug Transporter Cdr1

Synthetic Organotellurium Compounds Sensitize Drug-Resistant Candida albicans Clinical Isolates to Fluconazole

Contact Info

Product

Resources

About