Jakab Ágnes, Emri Tamás, Csillag Kinga, Szabó Anita, Nagy Fruzsina, Baranyai Edina, Sajtos Zsófi, Géczi Dóra, Antal Károly, Kovács Renátó, Szabó Krisztina, Dombrádi Viktor, Pócsi István
Department of Molecular Biotechnology and Microbiology, Faculty of Science and Technology, University of Debrecen, 4032 Debrecen, Hungary.
Department of Medical Microbiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.
J Fungi (Basel). 2021 Jul 6;7(7):540. doi: 10.3390/jof7070540.
The glucocorticoid betamethasone (BM) has potent anti-inflammatory and immunosuppressive effects; however, it increases the susceptibility of patients to superficial infections. Previously we found that this disadvantageous side effect can be counteracted by menadione sodium bisulfite (MSB) induced oxidative stress treatment. The fungus specific protein phosphatase Z1 (CaPpz1) has a pivotal role in oxidative stress response of and was proposed as a potential antifungal drug target. The aim of this study was to investigate the combined effects of gene deletion and MSB treatment in BM pre-treated cultures. We found that the combined treatment increased redox imbalance, enhanced the specific activities of antioxidant enzymes, and reduced the growth in cappz1 mutant (KO) strain. RNASeq data demonstrated that the presence of BM markedly elevated the number of differentially expressed genes in the MSB treated KO cultures. Accumulation of reactive oxygen species, increased iron content and fatty acid oxidation, as well as the inhibiting ergosterol biosynthesis and RNA metabolic processes explain, at least in part, the fungistatic effect caused by the combined stress exposure. We suggest that the synergism between MSB treatment and CaPpz1 inhibition could be considered in developing of a novel combinatorial antifungal strategy accompanying steroid therapy.
糖皮质激素倍他米松（BM）具有强大的抗炎和免疫抑制作用；然而，它会增加患者发生浅表感染的易感性。此前我们发现，甲萘醌亚硫酸氢钠（MSB）诱导的氧化应激处理可以抵消这种不利的副作用。真菌特异性蛋白磷酸酶Z1（CaPpz1）在[具体真菌名称未给出]的氧化应激反应中起关键作用，并被提议作为潜在的抗真菌药物靶点。本研究的目的是探讨在BM预处理的[具体真菌名称未给出]培养物中基因缺失与MSB处理的联合效应。我们发现联合处理增加了氧化还原失衡，增强了抗氧化酶的比活性，并降低了cappz1突变体（KO）菌株的生长。RNA测序数据表明，BM的存在显著增加了MSB处理的KO培养物中差异表达基因的数量。活性氧的积累、铁含量增加和脂肪酸氧化，以及对麦角甾醇生物合成和RNA代谢过程的抑制，至少部分解释了联合应激暴露所导致的抑菌作用。我们建议，在开发伴随类固醇治疗的新型联合抗真菌策略时，可以考虑MSB处理与CaPpz1抑制之间的协同作用。
