Moitra Samrat, Mukherjee Sumit, Hernandez Veronica L, Zhang Kai
Department of Biological Sciences, Texas Tech University, Lubbock, TX 79409, USA.
Int J Mol Sci. 2025 Aug 31;26(17):8473. doi: 10.3390/ijms26178473.
Sterol biosynthesis is crucial for the function of biological membranes and an important target for anti-protozoan/anti-fungal drugs. In the trypanosomatid parasite , the deletion of sterol C14-demethylase (C14DM) results in hypersensitivity to heat, increased plasma membrane fluidity, profound mitochondrial dysfunctions, and reduced virulence in mice. In this study, we show that C14DM-null mutants are defective in their tolerance to membrane-disrupting agents and osmotic stress and their ability to form autophagosomes. In addition, C14DM-null mutants exhibit a heightened sensitivity to anti-trypanosomatid drugs including antimony, ethidium bromide, and pentamidine. The combination of itraconazole (a C14DM antagonist) and pentamidine synergistically inhibits the growth of parasites. These findings reveal new insight into the roles of sterol synthesis in protozoan pathogens and highlight the potential of using drug combinations to achieve better treatment outcomes.
甾醇生物合成对于生物膜的功能至关重要，并且是抗原生动物/抗真菌药物的重要靶点。在锥虫寄生虫中，甾醇C14-脱甲基酶（C14DM）的缺失导致对热敏感、质膜流动性增加、严重的线粒体功能障碍以及小鼠毒力降低。在本研究中，我们表明C14DM基因缺失突变体在对膜破坏剂和渗透压应激的耐受性以及形成自噬体的能力方面存在缺陷。此外，C14DM基因缺失突变体对包括锑、溴化乙锭和喷他脒在内的抗锥虫药物表现出更高的敏感性。伊曲康唑（一种C14DM拮抗剂）和喷他脒联合使用可协同抑制寄生虫的生长。这些发现揭示了甾醇合成在原生动物病原体中的新作用，并突出了使用联合药物实现更好治疗效果的潜力。
