Mitochondrial dysfunctions trigger the calcium signaling-dependent fungal multidrug resistance.
Yeqi LiYuanwei ZhangChi ZhangHongchen WangXiaolei WeiPeiying ChenLing LuPublished in: Proceedings of the National Academy of Sciences of the United States of America (2019)
Drug resistance in fungal pathogens has risen steadily over the past decades due to long-term azole therapy or triazole usage in agriculture. Modification of the drug target protein to prevent drug binding is a major recognized route to induce drug resistance. However, mechanisms for nondrug target-induced resistance remain only loosely defined. Here, we explore the molecular mechanisms of multidrug resistance resulted from an efficient adaptation strategy for survival in drug environments in the human pathogen Aspergillus fumigatus We show that mutants conferring multidrug resistance are linked with mitochondrial dysfunction induced by defects in heme A biosynthesis. Comparison of the gene expression profiles between the drug-resistant mutants and the parental wild-type strain shows that multidrug-resistant transporters, chitin synthases, and calcium-signaling-related genes are significantly up-regulated, while scavenging mitochondrial reactive oxygen species (ROS)-related genes are significantly down-regulated. The up-regulated-expression genes share consensus calcium-dependent serine threonine phosphatase-dependent response elements (the binding sites of calcium-signaling transcription factor CrzA). Accordingly, drug-resistant mutants show enhanced cytosolic Ca2+ transients and persistent nuclear localization of CrzA. In comparison, calcium chelators significantly restore drug susceptibility and increase azole efficacy either in laboratory-derived or in clinic-isolated A. fumigatus strains. Thus, the mitochondrial dysfunction as a fitness cost can trigger calcium signaling and, therefore, globally up-regulate a series of embedding calcineurin-dependent-response-element genes, leading to antifungal resistance. These findings illuminate how fitness cost affects drug resistance and suggest that disruption of calcium signaling might be a promising therapeutic strategy to fight against nondrug target-induced drug resistance.
Keyphrases
- drug resistant
- multidrug resistant
- transcription factor
- acinetobacter baumannii
- wild type
- gram negative
- reactive oxygen species
- candida albicans
- drug induced
- genome wide
- oxidative stress
- physical activity
- endothelial cells
- genome wide identification
- escherichia coli
- dna damage
- dna methylation
- high glucose
- primary care
- body composition
- binding protein
- climate change
- bone marrow
- stem cells
- diabetic rats
- cell death
- cystic fibrosis
- adverse drug
- dna binding
- clinical practice
- replacement therapy
- mesenchymal stem cells
- small molecule
- cell wall
- smoking cessation
- copy number
- protein protein
- genome wide analysis