Love Sierra L, McKeon Megan C, Vollmer Henrik, Paulson Joshua C, Oshimura Nanami, Valentine Olivia, Ortiz Sébastien C, Hull Christina M, Hoskins Aaron A
Genetics Training Program, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA.
mSphere. 2025 Jun 23:e0024825. doi: 10.1128/msphere.00248-25.
is an opportunistic fungal pathogen responsible for life-threatening infections, particularly in immunocompromised individuals. The limitations of current antifungal therapies due to toxicity and the emergence of resistance highlight the need for novel treatment strategies and targets. has an intron-rich genome, and pre-mRNA splicing is required for expression of the vast majority of its genes. In this study, we investigated the efficacy of a human splicing inhibitor, pladienolide B (PladB), as an antifungal against . PladB inhibited the growth of in liquid culture and spore germination. The potency of PladB could be increased by simultaneous treatment with either FK506 or clorgyline. This combination treatment resulted in significant reductions in fungal growth and prevented spore germination. Transcriptomic analysis revealed that PladB inhibits splicing in and results in widespread intron retention. In combination with FK506, this resulted in downregulation of or intron retention in transcripts from processes vital for cellular growth, including translation, transcription, and RNA processing. Together, these results suggest that targeting RNA splicing pathways could be a promising antifungal strategy and that the effectiveness of splicing inhibitors as antifungals can be increased by co-administering drugs such as FK506.IMPORTANCEFungal infections, like those caused by , can turn deadly for many patients. New treatments and therapeutic targets are needed to combat these pathogens. One potential target is the pre-mRNA processing pathway, which is required for expression of nearly all protein-coding genes in . We have determined that a pre-mRNA splicing inhibitor can inhibit both growth and germination and that the potency of this drug can be increased when used in combination with other molecules. This work provides evidence that targeting steps in pre-mRNA processing may be an effective antifungal strategy and avenue for the development of new medicines.
是一种机会性真菌病原体，可导致危及生命的感染，尤其是在免疫功能低下的个体中。由于毒性和耐药性的出现，当前抗真菌疗法存在局限性，这凸显了对新型治疗策略和靶点的需求。具有富含内含子的基因组，绝大多数基因的表达都需要前体mRNA剪接。在本研究中，我们研究了一种人类剪接抑制剂普拉地诺醇B（PladB）作为抗真菌药物对的疗效。PladB抑制了在液体培养中的生长和孢子萌发。同时用FK506或氯吉宁处理可提高PladB的效力。这种联合处理导致真菌生长显著减少并阻止了孢子萌发。转录组分析表明，PladB抑制中的剪接并导致广泛的内含子保留。与FK506联合使用时，这导致对细胞生长至关重要的过程（包括翻译、转录和RNA加工）的转录本中的或内含子保留下调。总之，这些结果表明靶向RNA剪接途径可能是一种有前景的抗真菌策略，并且通过共同施用FK506等药物可以提高剪接抑制剂作为抗真菌药物的有效性。重要性真菌感染，如由引起的感染，对许多患者可能致命。需要新的治疗方法和治疗靶点来对抗这些病原体。一个潜在的靶点是前体mRNA加工途径，这是中几乎所有蛋白质编码基因表达所必需的。我们已经确定一种前体mRNA剪接抑制剂可以抑制生长和萌发，并且当与其他分子联合使用时该药物的效力可以提高。这项工作提供了证据，表明靶向前体mRNA加工步骤可能是一种有效的抗真菌策略和开发新药的途径。
