title: ABC transporters coupled with the elevated ergosterol contents contribute to the azole resistance and amphotericin B susceptibility.
abstract: Most screening approaches produce compounds that target survival genes and are likely to generate resistance over time. Simply having more drugs does not address the potential emergence of resistance caused by target mutation, drug efflux pumps over-expression, and so on. There is a great need to explore new strategies to treat fungal infections caused by drug-resistant pathogens. In this study, we found that azole-resistant Candida albicans with CaCDR1 and CaCDR2 over-expression is hypersensitive against amphotericin B (AmB) by our high throughput synergy screening (HTSS). In contrast, Δcdr1 and Δcdr2 knockout strains were resistant to AmB. Moreover, clinical isolates with increased expression of CaCDR1 and CaCDR2 demonstrated susceptibility to AmB, which can also synergize with the efflux pumps inducer fluphenazine (FPZ). Finally, the increased drug susceptibility to AmB in azole-resistant C. albicans with drug efflux pumps over-expression was consistent with the elevated expression of CaERG11 and its associated ergosterols in clinical isolates. Our data implies that the level of ergosterol contents determines the susceptibility to azoles and AmB in C. albicans. Deep understanding of the above mechanisms would offer new hope to treat drug-resistant C. albicans.
authors.affiliation: Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100190, China.
authors.forename: Biao
authors.initials: B
authors.lastname: Ren
authors.forename: Huan-Qin
authors.initials: HQ
authors.lastname: Dai
authors.forename: Gang
authors.initials: G
authors.lastname: Pei
authors.forename: Yao-Jun
authors.initials: YJ
authors.lastname: Tong
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhuo
authors.forename: Na
authors.initials: N
authors.lastname: Yang
authors.forename: Meng-Yi
authors.initials: MY
authors.lastname: Su
authors.forename: Pei
authors.initials: P
authors.lastname: Huang
authors.forename: Yu-Zhuo
authors.initials: YZ
authors.lastname: Yang
authors.forename: Li-Xin
authors.initials: LX
authors.lastname: Zhang
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000666:Amphotericin B / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D001393:Azoles / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects*; D025141:Drug Resistance, Fungal; D004357:Drug Synergism; D004875:Ergosterol / Q000378:metabolism*; D005476:Fluphenazine / Q000494:pharmacology
chemical_list: D018528:ATP-Binding Cassette Transporters; D000935:Antifungal Agents; D001393:Azoles; D000666:Amphotericin B; D005476:Fluphenazine; D004875:Ergosterol