title: Quinone derivatives isolated from the endolichenic fungus Phialocephala fortinii are Mdr1 modulators that combat azole resistance in Candida albicans.
abstract: One of the main azole-resistance mechanisms in Candida pathogens is the upregulation of drug efflux pumps, which compromises the efficacy of azoles and results in treatment failure. The combination of azole-antifungal agents with efflux pump inhibitors represents a promising strategy to combat fungal infection. High-throughput screening of 150 extracts obtained from endolichenic fungal cultures led to the discovery that the extract of Phialocephala fortinii exhibits potent activity for the reversal of azole resistance. From P. fortinii cultures, a total of 15 quinone derivatives, comprising 11 new derivatives and 4 known compounds, were obtained. Among these compounds, palmarumycin P3 (3) and phialocephalarin B (8) specifically modulate the expression of MDR1 to inhibit the activity of drug efflux pumps and therefore reverse azole resistance. The present study revealed Mdr1 targeting as an alternative mechanism for the discovery of new agents to fight antifungal drug resistance.
authors.affiliation: Department of Natural Product Chemistry, Key Lab of Chemical Biology of the Ministry of Education, Shandong University, No. 44 West Wenhua Road, Jinan City, Shandong Province, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Xie
authors.affiliation: Department of Natural Product Chemistry, Key Lab of Chemical Biology of the Ministry of Education, Shandong University, No. 44 West Wenhua Road, Jinan City, Shandong Province, China.
authors.forename: Wenqiang
authors.initials: W
authors.lastname: Chang
authors.affiliation: Department of Natural Product Chemistry, Key Lab of Chemical Biology of the Ministry of Education, Shandong University, No. 44 West Wenhua Road, Jinan City, Shandong Province, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Natural Product Chemistry, Key Lab of Chemical Biology of the Ministry of Education, Shandong University, No. 44 West Wenhua Road, Jinan City, Shandong Province, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Natural Product Chemistry, Key Lab of Chemical Biology of the Ministry of Education, Shandong University, No. 44 West Wenhua Road, Jinan City, Shandong Province, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Natural Product Chemistry, Key Lab of Chemical Biology of the Ministry of Education, Shandong University, No. 44 West Wenhua Road, Jinan City, Shandong Province, China.
authors.forename: Hongzhuo
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Natural Product Chemistry, Key Lab of Chemical Biology of the Ministry of Education, Shandong University, No. 44 West Wenhua Road, Jinan City, Shandong Province, China.
authors.forename: Sha
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Department of Natural Product Chemistry, Key Lab of Chemical Biology of the Ministry of Education, Shandong University, No. 44 West Wenhua Road, Jinan City, Shandong Province, China.
authors.forename: Hongxiang
authors.initials: H
authors.lastname: Lou
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000935:Antifungal Agents / Q000494:pharmacology*; D001203:Ascomycota / Q000737:chemistry*; D001393:Azoles / Q000494:pharmacology*; D016227:Benzoquinones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects* / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D025141:Drug Resistance, Fungal / Q000187:drug effects*; D018432:Drug Resistance, Multiple / Q000187:drug effects; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000187:drug effects; D057166:High-Throughput Screening Assays; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000935:Antifungal Agents; D001393:Azoles; D016227:Benzoquinones; D001688:Biological Products; C004532:quinone