Clemente de Moraes Daniel, do Carmo Freire Ribeiro Pinto Maria, Tenório Sousa Domingos Levy, do Valle Pereira Midlej Victor, Ferreira-Pereira Antônio
Avenida Carlos Chagas Filho 373, Laboratório de Bioquímica Microbiana, Instituto de Microbiologia Paulo de Góes, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro, RJ CEP: 21941-590, Brazil.
Avenida Carlos Chagas Filho 373, Laboratório de Química Heterocíclica, Instituto de Pesquisas de Produtos Naturais, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro, RJ CEP: 21941-590, Brazil.
Bioorg Med Chem. 2022 Jun 1;63:116749. doi: 10.1016/j.bmc.2022.116749. Epub 2022 Apr 14.
Infections caused particularly by Candida glabrata are hard to treat due to the development of antifungal resistance that occurs mainly through the production of efflux pumps and biofilm. Thus, a promising strategy to overcome infections caused by C. glabrata could be to use a substance able to inhibit efflux pumps and eradicate biofilms. Lapachones are natural naphthoquinones that possess a variety of pharmacological properties. Previous studies show that these substances inhibit the growth, virulence factors and efflux pumps of C. albicans. The aim of the present study was to evaluate whether lapachones are able to inhibit efflux pumps related to antifungal resistance in C. glabrata and either prevent biofilm formation or affect mature biofilms. Assays were performed with Saccharomyces cerevisiae strains that overexpress C. glabrata transporters (CgCdr1p and CgCdr2p). One C. glabrata clinical isolate that overexpresses CgCdr1p was also used. Both β-lapachone and β-nor-lapachone affected the growth of S. cerevisiae and C. glabrata when combined to fluconazole, and this action was inhibited by ascorbic acid. Both lapachones stimulated ROS production, inhibited efflux activity, adhesion, biofilm formation and the metabolism of mature biofilms of C. glabrata. Data obtained on the present study point to the potential use of β-lapachone and β-nor-lapachone as antibiofilm agents and adjuvants on the antifungal therapy related to resistant infections caused by C. glabrata.
特别是由光滑念珠菌引起的感染很难治疗，因为抗真菌耐药性的产生主要是通过外排泵和生物膜的形成。因此，一种有前景的克服光滑念珠菌感染的策略可能是使用一种能够抑制外排泵并根除生物膜的物质。拉帕醌是具有多种药理特性的天然萘醌。先前的研究表明，这些物质能抑制白色念珠菌的生长、毒力因子和外排泵。本研究的目的是评估拉帕醌是否能够抑制与光滑念珠菌抗真菌耐药性相关的外排泵，并预防生物膜形成或影响成熟生物膜。实验是用过量表达光滑念珠菌转运蛋白（CgCdr1p和CgCdr2p）的酿酒酵母菌株进行的。还使用了一种过量表达CgCdr1p的光滑念珠菌临床分离株。当与氟康唑联合使用时，β-拉帕醌和β-去甲拉帕醌都会影响酿酒酵母和光滑念珠菌的生长，而这种作用会被抗坏血酸抑制。两种拉帕醌都能刺激活性氧的产生，抑制外排活性、黏附、生物膜形成以及光滑念珠菌成熟生物膜的代谢。本研究获得的数据表明，β-拉帕醌和β-去甲拉帕醌有可能作为抗生物膜剂和抗真菌治疗辅助剂，用于治疗由光滑念珠菌引起的耐药感染。
