Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Engineering and Technology Research Centre for Microbiology, College of Life Sciences, Nanjing Normal Universitygrid.260474.3, Nanjing, China.
Microbiol Spectr. 2022 Jun 29;10(3):e0112122. doi: 10.1128/spectrum.01121-22. Epub 2022 Jun 8.
Fungal diseases have become a major public health issue worldwide. Increasing drug resistance and the limited number of available antifungals result in high morbidity and mortality. Metal-based drugs have been reported to be therapeutic agents against major protozoan diseases, but knowledge of their ability to function as antifungals is limited. In this study, we found that calcium supplementation combined with iron deficiency causes dramatic growth inhibition of the human fungal pathogens Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans. Calcium induces the downregulation of iron uptake-related genes and, in particular, causes a decrease in the expression of the transcription factor HapX, which tends to transcriptionally activate siderophore-mediated iron acquisition under iron-deficient conditions. Iron deficiency causes calcium overload and the overproduction of intracellular reactive oxygen species (ROS), and perturbed ion homeostasis suppresses fungal growth. These phenomena are consistently identified in azole-resistant A. fumigatus isolates. The findings here imply that low iron availability lets cells mistakenly absorb calcium as a substitute, causing calcium abnormalities. Thus, there is a mutual effect between iron and calcium in fungal pathogens, and the combination of calcium with an iron chelator could serve to improve antifungal therapy. Millions of immunocompromised people are at a higher risk of developing different types of severe fungal diseases. The limited number of antifungals and the emergence of antimicrobial resistance highlight an urgent need for new strategies against invasive fungal infections. Here, we report that calcium can interfere with iron absorption of fungal pathogens, especially in iron-limited environments. Thus, a combination of calcium supplementation with an iron chelator inhibits the growth of human fungal pathogens, including Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans. Moreover, we demonstrate that iron deficiency induces a nonspecific calcium uptake response, which results in toxic levels of metal. Findings in this study suggest that a microenvironment with excess calcium and limited iron is an efficient strategy to curb the growth of fungal pathogens, especially for drug-resistant isolates.
真菌病已成为全球主要的公共卫生问题。不断增加的药物耐药性和有限数量的可用抗真菌药物导致高发病率和死亡率。据报道，金属基药物是治疗主要原生动物疾病的治疗剂，但它们作为抗真菌药物的能力知之甚少。在这项研究中，我们发现钙补充剂与缺铁相结合会导致人类真菌病原体烟曲霉、白念珠菌和新生隐球菌的生长受到显著抑制。钙诱导铁摄取相关基因的下调，特别是导致转录因子 HapX 的表达减少，HapX 在缺铁条件下往往会转录激活铁载体介导的铁摄取。缺铁会导致钙超载和细胞内活性氧（ROS）的过度产生，而离子平衡的紊乱会抑制真菌的生长。这些现象在唑类耐药烟曲霉分离株中一致被发现。这些发现表明，低铁含量会使细胞错误地吸收钙作为替代品，导致钙异常。因此，铁和钙在真菌病原体中存在相互作用，钙与铁螯合剂的联合使用可以改善抗真菌治疗。数以百万计的免疫功能低下的人患不同类型严重真菌感染的风险更高。抗真菌药物的数量有限和抗菌药物耐药性的出现突出表明迫切需要针对侵袭性真菌感染的新策略。在这里，我们报告钙可以干扰真菌病原体的铁吸收，特别是在缺铁环境中。因此，钙补充剂与铁螯合剂的联合使用可以抑制人类真菌病原体的生长，包括烟曲霉、白念珠菌和新生隐球菌。此外，我们证明缺铁会诱导非特异性钙摄取反应，从而导致金属毒性水平升高。本研究的结果表明，富含钙和缺铁的微环境是抑制真菌病原体生长的有效策略，特别是对耐药分离株。
