de Moraes Daniel Clemente, Tessis Ana Claudia, Rollin-Pinheiro Rodrigo, Princival Jefferson Luiz, Villar José Augusto Ferreira Perez, Barbosa Leandro Augusto, Barreto-Bergter Eliana, Ferreira-Pereira Antônio
Departamento de Microbiologia Geral, Instituto de Microbiologia Paulo de Góes, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Cidade Universitária, Avenida Carlos Chagas Filho 373, Rio de Janeiro 21941-590, Brazil.
Instituto Federal do Rio de Janeiro, Rua Senador Furtado 121, Rio de Janeiro 20270-021, Brazil.
J Fungi (Basel). 2022 Jul 25;8(8):769. doi: 10.3390/jof8080769.
The poor outcome of treatments for fungal infections is a consequence of the increasing incidence of resistance to antifungal agents, mainly due to the overexpression of efflux pumps. To surpass this mechanism of resistance, a substance able to inhibit these pumps could be administered in association with antifungals. possesses an efflux pump (Pdr5p) homologue to those found in pathogenic yeast. Digoxin is a natural product that inhibits Na, K-ATPase. The aim of this study was to evaluate whether digoxin and its derivatives (i.e., DGB, digoxin benzylidene) can inhibit Pdr5p, reversing the resistance to fluconazole in yeasts. An mutant strain that overexpresses Pdr5p was used in the assays. The effects of the compounds on yeast growth, efflux activity, and Pdr5p ATPase activity were measured. All derivatives enhanced the antifungal activity of fluconazole against , in comparison to fluconazole alone, with FICI values ranging from 0.031 to 0.500. DGB 1 and DGB 3 presented combined effects with fluconazole against a strain, with fractional inhibitory concentration index (FICI) values of 0.625 and 0.281, respectively The compounds also inhibited the efflux of rhodamine 6G and Pdr5p ATPase activity, with IC values ranging from 0.41 μM to 3.72 μM. The results suggest that digoxin derivatives impair Pdr5p activity. Considering the homology between Pdr5p and efflux pumps from pathogenic fungi, these compounds are potential candidates to be used in association with fluconazole to treat resistant fungal infections.
真菌感染治疗效果不佳是抗真菌药物耐药性发生率不断上升的结果，主要原因是外排泵的过度表达。为了克服这种耐药机制，可以将一种能够抑制这些泵的物质与抗真菌药物联合使用。[研究对象]拥有一种与致病性酵母中发现的外排泵（Pdr5p）同源的外排泵。地高辛是一种抑制钠钾ATP酶的天然产物。本研究的目的是评估地高辛及其衍生物（即DGB、地高辛亚苄基）是否能够抑制Pdr5p，逆转酵母对氟康唑的耐药性。实验中使用了一种过表达Pdr5p的突变菌株。测量了这些化合物对酵母生长、外排活性和Pdr5p ATP酶活性的影响。与单独使用氟康唑相比，所有衍生物均增强了氟康唑对[研究对象]的抗真菌活性，FICI值范围为0.031至0.500。DGB 1和DGB 3与氟康唑联合作用于[研究对象]菌株，分数抑制浓度指数（FICI）值分别为0.625和0.281。这些化合物还抑制了罗丹明6G的外排和Pdr5p ATP酶活性，IC值范围为0.41μM至3.72μM。结果表明，地高辛衍生物会损害Pdr5p的活性。考虑到Pdr5p与致病真菌外排泵之间的同源性，这些化合物是与氟康唑联合用于治疗耐药真菌感染的潜在候选药物。
