Screening of chemical libraries for new antifungal drugs against Aspergillus fumigatus reveals the potential mechanism of action of miltefosine

Aspergillus fumigatus is an important fungal pathogen responsible for the development of aspergillosis, a disease characterized by a noninvasive process in immunocompetent hosts while in immunocompromised patients it tends to progress to a more severe clinical manifestation called invasive pulmonary aspergillosis (IPA). Miltefosine, a drug mainly used in the treatment of visceral and cutaneous leishmaniasis, displayed fungicidal activity against A. fumigatus. We screened an A. fumigatus transcription factor null library and identified a single mutant which the gene deletion (rmiA, resistant to miltefosine) conferring a phenotype of susceptibility to miltefosine. By using transcriptional profiling (RNA-seq) of the wild-type and the deltarmiA strains exposed to miltefosine, and Chromatin Immunoprecipitation coupled to next generation sequencing (ChIP-Seq) of RmiA, we identified differentially expressed genes directly or indirectly modulated by RmiA.