Synergistic Antifungal Effect of a Combination of Iron Deficiency and Calcium Supplementation
ABSTRACT 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...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2022-06-01
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| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.01121-22 |
| _version_ | 1811333185413316608 |
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| author | Jing Ye Yamei Wang Xinyu Li Qinyi Wan Yuanwei Zhang Ling Lu |
| author_facet | Jing Ye Yamei Wang Xinyu Li Qinyi Wan Yuanwei Zhang Ling Lu |
| author_sort | Jing Ye |
| collection | DOAJ |
| description | ABSTRACT 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. |
| first_indexed | 2024-04-13T16:49:18Z |
| format | Article |
| id | doaj.art-4b6b5962eeae43b1b584a8ac4820b09a |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-04-13T16:49:18Z |
| publishDate | 2022-06-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-4b6b5962eeae43b1b584a8ac4820b09a2022-12-22T02:39:00ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972022-06-0110310.1128/spectrum.01121-22Synergistic Antifungal Effect of a Combination of Iron Deficiency and Calcium SupplementationJing Ye0Yamei Wang1Xinyu Li2Qinyi Wan3Yuanwei Zhang4Ling Lu5Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Engineering and Technology Research Centre for Microbiology, College of Life Sciences, Nanjing Normal University, Nanjing, ChinaJiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Engineering and Technology Research Centre for Microbiology, College of Life Sciences, Nanjing Normal University, Nanjing, ChinaJiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Engineering and Technology Research Centre for Microbiology, College of Life Sciences, Nanjing Normal University, Nanjing, ChinaJiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Engineering and Technology Research Centre for Microbiology, College of Life Sciences, Nanjing Normal University, Nanjing, ChinaJiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Engineering and Technology Research Centre for Microbiology, College of Life Sciences, Nanjing Normal University, Nanjing, ChinaJiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Engineering and Technology Research Centre for Microbiology, College of Life Sciences, Nanjing Normal University, Nanjing, ChinaABSTRACT 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.https://journals.asm.org/doi/10.1128/spectrum.01121-22Aspergillus fumigatusantifungal therapycalciumiron |
| spellingShingle | Jing Ye Yamei Wang Xinyu Li Qinyi Wan Yuanwei Zhang Ling Lu Synergistic Antifungal Effect of a Combination of Iron Deficiency and Calcium Supplementation Microbiology Spectrum Aspergillus fumigatus antifungal therapy calcium iron |
| title | Synergistic Antifungal Effect of a Combination of Iron Deficiency and Calcium Supplementation |
| title_full | Synergistic Antifungal Effect of a Combination of Iron Deficiency and Calcium Supplementation |
| title_fullStr | Synergistic Antifungal Effect of a Combination of Iron Deficiency and Calcium Supplementation |
| title_full_unstemmed | Synergistic Antifungal Effect of a Combination of Iron Deficiency and Calcium Supplementation |
| title_short | Synergistic Antifungal Effect of a Combination of Iron Deficiency and Calcium Supplementation |
| title_sort | synergistic antifungal effect of a combination of iron deficiency and calcium supplementation |
| topic | Aspergillus fumigatus antifungal therapy calcium iron |
| url | https://journals.asm.org/doi/10.1128/spectrum.01121-22 |
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