Functional insight into cyclin-dependent kinase (CDK)7 via chemical inhibition of the priority fungal pathogen <i>Cryptococcus neoformans</i>

<i>Cn</i>, a basidiomycete causing meningoencephalitis with 40%-60% mortality, was recently assigned as a "critical" priority pathogen by the World Health Organization. <i>Cn</i> commonly affects AIDS patients, organ transplant recipients, and individuals with hematological malignancies, yet current treatments are limited by toxicity or resistance due to prolonged therapy. Given that CDK7 inhibitors kill leukemia cells, and Cn proliferation in host tissues mimics tumor-like growth, we investigated whether their utility as anticancer agents extends to antifungal activity and elucidation of CDK7 function in <i>Cn</i>. Use of SY-1365, which was both antifungal and CnCDK7 inhibitory, identified roles for CnCDK7 in all stages of transcription, mRNA splicing, and cell cycle regulation. The antifungal activity of SY-1365 was also markedly enhanced in combination with membrane-targeting antifungals. Together, our findings highlight CDK7 inhibitors as valuable tools to study CDK7 function in Cn and as potentially promising antifungals in combination with licensed antifungals.