Synergistic interactions between β-lapachone and fluconazole in the inhibition of CaCdr2p and CaMdr1p in Candida albicans

IF 1.5 4区 生物学 Q4 MYCOLOGY
Daniel Clemente Moraes , Leandro Figueira Reis de Sá , Levy Tenorio Sousa Domingos , Maria do Carmo Freire Ribeiro Pinto , Rosangela Maria de Araújo Soares , Antônio Ferreira-Pereira
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引用次数: 3

Abstract

Background

Mortality rate of invasive Candida infections is raising mainly amongst immunocompromised patients. These infections are hard-to-treat mainly due to the increasing incidence of resistance. The overexpression of ATP-binding cassette and major facilitator superfamily transporters is the main responsible for the failure of antifungal therapies. In a Saccharomyces cerevisiae model, β-lapachone inhibited Pdr5p, a transporter homologous to those found in Candida albicans.

Aims

To determine whether β-lapachone reverses the resistance phenotype mediated by efflux transporters in C. albicans clinical isolates.

Methods

The antifungal activity of β-lapachone combined with fluconazole was measured by agarose chemosensitization and microdilution assays. CaCdr2p and CaMdr1p activities were evaluated through fluorescent dyes accumulation. ATPase activity was assessed using transporter-enriched plasma membranes.

Results

β-lapachone reverted antifungal resistance of S. cerevisiae and C. albicans strains overexpressing CaCdr2p and CaMdr1p transporters by inhibiting these proteins activities. CaCdr2p ATPase activity was not impaired by the compound.

Conclusions

β-lapachone is a promising drug candidate to be used as an adjuvant in the treatment of candidiasis caused by fluconazole-resistant C. albicans strains.

β-拉帕酮与氟康唑对白色念珠菌CaCdr2p和CaMdr1p抑制的协同作用
背景:侵袭性念珠菌感染的死亡率主要在免疫功能低下的患者中上升。这些感染难以治疗,主要是由于耐药发生率增加。atp结合盒和主要促进剂超家族转运蛋白的过表达是抗真菌治疗失败的主要原因。在酿酒酵母模型中,β-lapachone抑制Pdr5p,一种与白色念珠菌同源的转运体。目的探讨β-lapachone能否逆转白念珠菌临床分离株外排转运体介导的耐药表型。方法采用琼脂糖化学增敏法和微量稀释法测定β-拉帕酮与氟康唑联合抑菌活性。通过荧光染料积累法测定CaCdr2p和CaMdr1p活性。利用富含转运蛋白的质膜评估atp酶活性。结果β-lapachone通过抑制CaCdr2p和CaMdr1p转运体的活性,恢复了酿酒葡萄球菌和白色念珠菌的抗真菌能力。CaCdr2p atp酶活性未被该化合物破坏。结论β-拉帕酮是治疗耐氟康唑白色念珠菌引起的念珠菌病的一种有前景的佐剂药物。
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来源期刊
CiteScore
1.90
自引率
0.00%
发文量
17
审稿时长
81 days
期刊介绍: Revista Iberoamericana de Micología (Ibero-American Journal of Mycology) is the official journal of the Asociación Española de Micología, Asociación Venezolana de Micología and Asociación Argentina de Micología (The Spanish, Venezuelan, and Argentinian Mycology Associations). The Journal gives priority to publishing articles on studies associated with fungi and their pathogenic action on humans and animals, as well as any scientific studies on any aspect of mycology. The Journal also publishes, in Spanish and in English, original articles, reviews, mycology forums, editorials, special articles, notes, and letters to the editor, that have previously gone through a scientific peer review process.
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