Department of Medicine, University of California San Diego, La Jolla, California, United States of America.
Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, United States of America.
PLoS One. 2024 Oct 1;19(10):e0308672. doi: 10.1371/journal.pone.0308672. eCollection 2024.
Trichomonas vaginalis is the causative agent of the common sexually transmitted disease, trichomoniasis, which affects more than a hundred million people worldwide. Metronidazole and tinidazole, agents belonging to the 5-nitroheterocyclic class of antimicrobials, are most often used to treat infection, but increased resistance has been reported and adverse effects of these drugs can be significant. Consequently, an urgent need exists for the development of novel drug entities against trichomoniasis. Critical for antimicrobial drug development is the demonstration of in vivo efficacy. Murine models of vaginal T. vaginalis infection are unreliable for unknown reasons. Meanwhile, murine infections with the related bovine pathogen, Tritrichomonas foetus, tend to be more robust, although susceptibility to different antimicrobials might differ from T. vaginalis. Here, we explored the utility of T. foetus infection as a surrogate model for drug development against T. vaginalis. Four different T. foetus strains caused robust vaginal infection in young mice, while none of four diverse T. vaginalis strains did. Comparison of drug susceptibility profiles revealed that T. foetus and T. vaginalis were similarly susceptible to a range of 5-nitroheterocyclic and gold(I) compounds. By comparison, proteasome inhibitors were 10- to 15-fold less active against T. foetus than T. vaginalis, although one of the proteasome inhibitors, bortezomib, had low micromolar activity or better against multiple strains of both trichomonads. Different strains of T. foetus were used to demonstrate the utility of the murine vaginal infection models for in vivo efficacy testing, including for bortezomib and a gold(I) compound. The differences in susceptibility to proteasome inhibitors may be partially explained by differences in the proteasome subunit sequences between the two trichomonads, although the functional relevance of the proteasome was similar in both organisms. These findings indicate that T. foetus can serve as a reliable surrogate model for T. vaginalis in vitro and in murine infections in vivo, but caution must be exercised for specific drug classes with targets, such as the proteasome, that may display genetic divergence between the trichomonads.
阴道毛滴虫是一种常见的性传播疾病——滴虫病的病原体，全球有超过 1 亿人受到感染。甲硝唑和替硝唑属于 5-硝基杂环类抗生素，是最常用于治疗感染的药物，但已报告出现耐药性，且这些药物的不良反应可能很显著。因此，迫切需要开发针对滴虫病的新型药物。对于抗菌药物的开发，关键在于证明体内疗效。由于未知原因，阴道毛滴虫感染的小鼠模型并不可靠。同时，与相关的牛病原体胎儿三毛滴虫的小鼠感染往往更具侵袭性，尽管对不同抗菌药物的敏感性可能与阴道毛滴虫不同。在这里，我们探讨了胎儿三毛滴虫感染作为针对阴道毛滴虫开发药物的替代模型的适用性。四种不同的胎儿三毛滴虫株在幼鼠中引起了强烈的阴道感染，而四种不同的阴道毛滴虫株均未引起感染。药敏谱比较显示，胎儿三毛滴虫和阴道毛滴虫对一系列 5-硝基杂环类和金（I）化合物均具有相似的敏感性。相比之下，蛋白酶体抑制剂对胎儿三毛滴虫的活性比阴道毛滴虫低 10-15 倍，尽管蛋白酶体抑制剂之一硼替佐米对两种毛滴虫的多个株系均具有低微摩尔活性或更好的活性。不同的胎儿三毛滴虫株被用于证明小鼠阴道感染模型在体内疗效测试中的适用性，包括硼替佐米和金（I）化合物。蛋白酶体抑制剂敏感性的差异可能部分解释为两种毛滴虫中蛋白酶体亚基序列的差异，尽管两种生物中蛋白酶体的功能相关性相似。这些发现表明，胎儿三毛滴虫可以作为阴道毛滴虫的可靠替代模型，用于体外和体内的小鼠感染，但对于蛋白酶体等具有靶点的特定药物类别，必须谨慎使用，因为这些靶点在两种毛滴虫之间可能存在遗传差异。
