Identification of possible miltefosine targets in Aspergillus fumigatus

• Grant number: 21/02883-3
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: May 01, 2021
• End date: April 30, 2022
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Gustavo Henrique Goldman
• Grantee: Maria Vitória de Lazari Fonseca
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Fungi until a few years ago were considered low dangerous for the health of humans. Currently, as a consequence of the immunological impairment of individuals, caused by diseases or prolonged use of medications, fungi have become clinically relevant, spreading and causing serious infections, being resistant to antifungals and causing fatal diseases. Among the most common fungal infections are those caused by fungi of the genus Candida and Aspergillus, which mainly affect people with the immune system weakened due to cancer, AIDS, extensive use of antibiotics, corticosteroids or invasive procedures such as probes and catheters in intensive care unit (ICU). The genus Aspergillus encompasses the species Aspergillus fumigatus, which is of interest in this study. A. fumigatus is a ubiquitous fungus, found in environments such as households, food, soils and swimming pools, among other places. Infection by this genus results from the inhalation of conidia present in the air and, among the various pathological forms caused by infection by A. fumigatus, pulmonary aspergillosis is the most frequent disease being Invasive Pulmonary Aspergillosis (API), the most aggressive form of the disease. The main method of API treatment is based on the use of azoles; however, resistance to this class of antifungalagents has increased vigorously in the last decade, which highlights the urgent need to develop new drugs. However, the development of new medicines is expensive, time consuming, complicated and requires years of testing to obtain approval and marketing. Thus, several strategies have been adopted to reverse this situation, with drug repositioning being a promising approach. Miltefosine, a drug intended for the treatment of visceral leishmaniasis (VL), has been identified as a drug with antifungal efficacy against several species of human pathogenic fungi. However, little is known about the mechanism of action of this drug and what is its mechanism of action. Recently, our group demonstrated that miltefosine presents efficient antifungal activity against A. fumigatus. We mapped, through the RNA and lipidomic sequencing method, the main events modulated in A. fumigatus when this fungus is exposed to miltefosine. Our results strongly suggest that the mechanism of action of miltefosine involves the biosynthesis pathway of sphingolipids and that the hfdA gene, homologous to the HFD1 gene of Saccharomyces cerevisiae, may be the target of miltefosin in A. fumigatus. Therefore, we propose to delete the hfdA gene of A. fumigatus and characterize the participation of this gene in events related to the use of miltefosine as antifungal. (AU)