Synergistic Antifungal Effect of a Combination of Iron Deficiency and Calcium Supplementation.
Synergistic Antifungal Effect of a Combination of Iron Deficiency and Calcium Supplementation.
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缺铁与补钙组合的协同抗真菌作用
DOI：
10.1128/spectrum.01121-22
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发表时间：
2022-06-29
影响因子：
3.7
通讯作者：
Lu, Ling
中科院分区：
文献类型：
--
作者：
Ye, Jing;Wang, Yamei;Li, Xinyu;Wan, Qinyi;Zhang, Yuanwei;Lu, Ling
真菌病已成为世界范围内的一个重大公共卫生问题。耐药性的增加和可用抗真菌药物的数量有限导致了高发病率和死亡率。据报道，基于金属的药物是治疗主要原虫疾病的药物，但对它们作为抗真菌药物的能力的了解有限。在这项研究中，我们发现补钙和缺铁对人体真菌病原体烟曲霉、白色念珠菌和新生隐球菌的生长有显著的抑制作用。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，在缺铁条件下，HapX往往在转录上激活铁载体介导的铁获取。缺铁导致钙超载和细胞内活性氧(ROS)的过量产生，而扰乱的离子稳态抑制真菌的生长。这些现象在耐唑烟曲霉菌分离株中得到了一致的确认。这里的发现暗示，铁的低利用率使细胞错误地吸收钙作为替代品，导致钙异常。因此，在真菌病原体中，铁和钙之间存在相互作用，而钙与铁络合剂的结合可能有助于改善抗真菌治疗。重要的是，数百万免疫受损的人患不同类型严重真菌疾病的风险更高。抗真菌药物的数量有限和出现抗菌素耐药性突出表明迫切需要针对侵袭性真菌感染制定新的战略。在这里，我们报告了钙可以干扰真菌病原体对铁的吸收，特别是在铁有限的环境中。因此，钙补充剂和铁络合剂的结合可以抑制人类真菌病原体的生长，包括烟曲霉、白色念珠菌和新生隐球菌。此外，我们还证明了缺铁会引起非特异性的钙摄取反应，从而导致金属中毒。这项研究的结果表明，钙过量而铁有限的微环境是抑制真菌病原体生长的有效策略，特别是对于耐药菌株。
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. IMPORTANCE 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.
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影响因子：
11.3
作者：
Gerwien F;Skrahina V;Kasper L;Hube B;Brunke S
通讯作者：
Brunke S
影响因子：
30.3
作者：
Chen C;Pande K;French SD;Tuch BB;Noble SM
通讯作者：
Noble SM
DOI：
10.1016/j.jtemb.2018.04.029
发表时间：
2018-01-01
影响因子：
3.5
作者：
Candia, Valeria;Rios-Castillo, Israel;Pizarro, Fernando
通讯作者：
Pizarro, Fernando
影响因子：
16.6
作者：
Deshpande CN;Ruwe TA;Shawki A;Xin V;Vieth KR;Valore EV;Qiao B;Ganz T;Nemeth E;Mackenzie B;Jormakka M
通讯作者：
Jormakka M
钙和ROS：相互互动。
影响因子：
11.4
作者：
Görlach A;Bertram K;Hudecova S;Krizanova O
通讯作者：
Krizanova O