Invasive fungal infections have risen steadily in recent decades due to the increasing number of immunodeficient and immunocompromised patients. According to the statistics of the Global Action Found for Fungal Infection, more than one billion people around the world are infected with the fungus in the superficial tissues such as skin and mucosa. Moreover approximately 150 people die every hour from the fungal infection, which obviously poses a great health threat to human. Azoles are recommended as the first-line medicine for the primary treatment of fungal infectious diseases. However, drug resistance in fungal pathogens has risen steadily due to long-term azole therapy or triazole usage in agriculture, which causes the decreased effects or the scarcity of antifungal drugs. For the resistant mechanism to azole antifungals observed in the fungal pathogen Aspergillus fumigatus, most scientists focus on the common mechanism Cyp51A mutation which results in the decreasing affinity of azoles for the Cyp51A protein. However, mechanisms for the increasing number of nondrug target-induced resistance remain only loosely defined. Recently, Dr Ling Lu’s group published their findings in the journal of “Proceedings of the National Academy of Sciences (PNAS). (https://www.pnas.org/content/early/2019/12/05/1911560116).
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. This finding shows 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 calciumsignaling-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 phosphatasedependent 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.
The first author is Yeqi Li, the Ph.D student in School of Life Science. The corresponding address is Nanjing Normal University.