Invasive fungal infections have risen steadily in recent decades due to the increasing number of immunocompromised patients. According to the statistics collected by the Global Action Fund for Fungal Infections(GAFFI), more than 1 billion people around the world have fungal infection problems on skin, mucous membranes and other shallow tissues, and there are about 150 people who die from fungal infections every hour, which means fungal infections pose a huge threat to the health and existence of human beings. Azoles are recommended as the first-line medicine for the primary treatment of fungal infections because of fewer side effects. However, drug resistance in fungal pathogens has risen steadily over the past several decades due to long-term azole therapy or triazole usage in agriculture. As a result, the effect of antifungal drugs has decreased drastically and the patients have no alternative drugs to use. People tend to focus on the drug target mutation when studying the emerging mechanism of antifungals, but mechanisms for nondrug target-induced resistance, especially the mechanisms of multidrug resistance, remain only loosely defined. Recently, the research group led by Professor Ling Lu of the School of Life Sciences at NNU has published the results of their study in PNAS.
This study revealed a widespread molecular mechanism of “fitness cost” among microbial resistant, and proved that effective inhibitors can be used to reverse drug resistance, which provides a promising approach and core strategy for coping with or reversing the drug resistance of pathogens in the environment or during clinical treatment.
In the process of drug treatment, some drug resistant pathogens are picked out. In the absence of the antifungal drug, a resistant isolate has a lower fitness than wild-type isolates. However, under long term drug treatment conditions, azole resistance is an efficient adaptation strategy of fungal pathogens in the human host or in the environment. This research showed that drug-resistant Aspergillus fumigatus presents mitochondrial dysfunction, resulting in lower fitness. Mitochondria not only are essential intracellular organelles for energy production, but also can sequester and release Ca2+ as a dynamic Ca2+ store. The mitochondrial dysfunction is an efficient adaptation strategy for survival in a drug environment. As the loss of part of the mitochondrial functions, calcium-signaling transcription factor CrzA, also known as crazy transcription factor for its varied functions, begins to work. Research evidence directly proved that CrzA improves drug resistance by up-regulating drug efflux pumps and chitin synthases. Although CrzA had been identified as an important multifunctional transcription factor, it’s the first time to prove that it has the function of changing mutant drug resistance by adjusting efflux pumps and controlling the environment inside of cells, living up to its reputation of “crazy”. This study revealed a widespread molecular mechanism of “fitness cost” among microbial resistant. All living things have the ability to survive in their surrounding environment and pass on their features to the next generation, including the ability to survive and reproduce. Under the condition of long term drug treatment, pathogens can become drug resistant. These mutants can continue to live and reproduce under drug treatment, but with lower adaptability. The study found the molecular mechanism behind mutation and proved that an effective inhibitor can be used to reverse drug resistance, which provides a promising approach and core strategy for coping with or reversing the drug resistance of pathogens in the environment or during clinical treatment. The picture illustrates the drug resistance mode of A. fumigatus and its regulating mechanism.
PhD candidate Yeqi Li, from the School of Life Sciences, is the first author and the corresponding authors are also from the School of Life Sciences at NNU.