The mitochondrial protein Bcs1A regulates antifungal drug tolerance by affecting efflux pump expression in the filamentous pathogenic fungus Aspergillus fumigatus

• DOI: 10.1128/spectrum.01172-24
• Publication Date: 2024-08-20T13:05:01Z
• Authors: Guorong Yang; Weiwei Shi; Wenlin He; Jing Wu; Sutao Huang; Li Mo; Junjie Zhang; Huaxue Wang; Xiaogang Zhou
• Keywords: Efflux; Antifungal drugs; Filamentous fungus; Antifungal drugs; Fungal pathogen; Pathogenic fungus; Fungal protein

ABSTRACT Aspergillus fumigatus is the predominant pathogen responsible for aspergillosis infections, with emerging drug-resistant strains complicating treatment strategies. The role of mitochondrial functionality in fungal resistance to antifungal agents well-documented yet not fully understood. In this study, protein Bcs1A, a homolog yeast Bcs1, was found regulate colony growth, ion homeostasis, and response drugs A. . Microscopic observations revealed substantial colocalization Bcs1A-GFP fusion fluorescence mitochondria. Bcs1A deletion compromised growth utilization non-fermentable carbon sources, alongside causing abnormal membrane potential reduced reactive oxygen species production. These findings underscore Bcs1A’s vital maintaining integrity. Phenotypic analysis determinations minimum inhibitory concentrations indicated that Δ bcs1A mutant more resistant various agents, such as azoles, terbinafine, simvastatin, compared wild-type strain. RNA sequencing RT-qPCR highlighted an upregulation multiple efflux pumps mutant. Furthermore, loss principal drug pump, mdr1, decreased azole tolerance Δbcs1A mutant, suggesting modulated azoles via pump expression. Collectively, these results establish essential responsiveness mediated through regulation. IMPORTANCE Drug presents formidable obstacle clinical management aspergillosis. Mitochondria are integral biochemical pathways, including those involved fungi response, making proteins promising therapeutic targets therapy. This study confirms respiratory chain protein, indispensable multidrug Mutation only leads series upregulated but also shows primary mdr1 , partial reduction highlighting significant influence on mitochondria-mediated resistance.