Microbial persisters, a subpopulation of genetically susceptible cells that are normally dormant and tolerant to antimicrobial agents, are considered to be an important contributor to recurrent infections and drug treatment failure. Despite its potential clinical importance, the formation of fungicide-tolerant fungal persisters has not been directly observed in vivo during fungal disease.
Recently, Dr. WANG Linqi’s group and Dr. Yu V Fu’s group from the Institute of Microbiology, Chinese Academy of Sciences, have demonstrated that the human fungal pathogen Cryptococcus neoformans can form persisters during lung infection that are highly tolerant to amphotericin B (AmB), the only approved fungicide for the treatment of cryptococcal infections. This work was published in Cell Host & Microbe.
A major bottleneck in the study of fungicide persistence is the lack of cell tracking methods to sort and assess the highly heterogeneous fungal cell subpopulations in vivo. By exploring stationary phase indicator molecules and developing single-cell tracking strategies, the authors showed that in the mouse lung, AmB persisters are highly enriched in cryptococcal cells that abundantly produce these molecules. AmB persistence in C. neoformans involves two parallel mechanisms: inhibition of energy metabolism and activation of antioxidant systems, in which a cryptococcal stationary phase antioxidant, ergothioneine, plays a central role. Remarkably, ergothioneine-mediated AmB persistence is conserved in different fungi. Furthermore, screening of a library of FDA-approved drugs reveals a specific efficacy of the antidepressant sertraline against cryptococcal persisters.
The study was done in collaboration with Tongji University, Southwest University, and Georgetown University. And this work was supported by grants from the National Key Research and Development Program, the National Natural Science Foundation of China, and the CAS Interdisciplinary Innovation Team.
Figure: Proposed model depicting the mechanisms underlying the formation of fungicide-tolerant persisters (Image by Dr. WANG Linqi's Group)
State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China