Inhibition of fungal ABC transporters by unnarmicin A and unnarmicin C, novel cyclic peptides from marine bacterium

Novel inhibitors of fungal ATP-binding cassette transporters were obtained by screening compounds and crude extracts from marine-derived fungi and bacteria using disk diffusion assays of Saccharomyces cerevisiae strains overexpressing a variety of fungal multi-drug efflux pumps. The cyclodepsipeptid...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2007-12, Vol.364 (4), p.990-995
Main Authors: Tanabe, Koichi, Lamping, Erwin, Adachi, Kyoko, Takano, Yukie, Kawabata, Kazutaka, Shizuri, Yoshikazu, Niimi, Masakazu, Uehara, Yoshimasa
Format: Article
Language:English
Subjects:
Antifungal azole
ATP-binding cassette transporter
ATP-Binding Cassette Transporters - antagonists & inhibitors
Bacteria
Candida albicans
Candida albicans - drug effects
Candida albicans - metabolism
Cyclodepsipeptide
Expression system
Marine Biology
Multi-drug resistance
Peptides, Cyclic - administration & dosage
Pump inhibitor
Saccharomyces cerevisiae
Saccharomyces cerevisiae - drug effects
Saccharomyces cerevisiae - metabolism
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Summary:Novel inhibitors of fungal ATP-binding cassette transporters were obtained by screening compounds and crude extracts from marine-derived fungi and bacteria using disk diffusion assays of Saccharomyces cerevisiae strains overexpressing a variety of fungal multi-drug efflux pumps. The cyclodepsipeptides unnarmicin A and unnarmicin C were able to sensitize cells overexpressing azole drug pumps ScPdr5p, CaCdr1p, CgCdr1p, and CgPdh1p to sub-MIC concentrations of fluconazole without affecting the growth of CaCdr2p and CaMdr1p overexpressing cells. Unnarmicin A and unnarmicin C were potent inhibitors of rhodamine 6G efflux of CaCdr1p expressing cells with IC 50 values of 3.61 and 5.65 μM, respectively. They inhibited the in vitro CaCdr1p ATPase activity at IC 50 values of 0.495 and 0.688 μM, respectively. And most importantly, they were able to sensitize azole-resistant Candida albicans clinical isolates to fluconazole. Unnarmicin A and unnarmicin C are candidate efflux pump inhibitors with the potential to be used as adjuvants for antifungal chemotherapy.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2007.10.110