Brain glucose induces tolerance of Cryptococcus neoformans to amphotericin B during meningitis
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Abstract
Antibiotic tolerance is the ability of a susceptible population to survive high doses of cidal drugs and has been shown to compromise therapeutic outcomes in bacterial infections. In comparison, whether fungicide tolerance can be induced by host-derived factors during fungal diseases remains largely unknown. Here, through a systematic evaluation of metabolite-drug-fungal interactions in the leading fungal meningitis pathogen, Cryptococcus neoformans, we found that brain glucose induces fungal tolerance to amphotericin B (AmB) in mouse brain tissue and patient cerebrospinal fluid via the fungal glucose repression activator Mig1. Mig1-mediated tolerance limits treatment efficacy for cryptococcal meningitis in mice via inhibiting the synthesis of ergosterol, the target of AmB, and promoting the production of inositolphosphorylceramide, which competes with AmB for ergosterol. Furthermore, AmB combined with an inhibitor of fungal-specific inositolphosphorylceramide synthase, aureobasidin A, shows better efficacy against cryptococcal meningitis in mice than do clinically recommended therapies.
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MDK99 and MDK99.99 can be used to detect fungicidal tolerance, such as tolerance of Cryptococcus neoformans to AmB.
“For fungicidal agents, MDK99 and MDK99.99 can also be used to detect fungicidal tolerance, such as detecting the tolerance of Cryptococcus neoformans to AmB [22].”
From Antifungal persistence: Clinical relevance and mechanisms (2025) · cites this paper as [22]
The fungal-specific IPC synthase inhibitor aureobasidin A enhances the efficacy of amphotericin B against Cryptococcus neoformans.
“The fungal-specific IPC synthase inhibitor aureobasidin A (AbA) enhances the efficacy of AMB against Cryptococcus neoformans34.”
From Candida auris skin tropism and antifungal resistance are mediated by carbonic anhydrase Nce103 (2025) · cites this paper as [34]
Growing evidence suggests that inositol phosphorylceramides contribute to amphotericin B tolerance.
“Growing evidence suggests that inositol phosphorylceramides (IPC) contribute to AMB tolerance34.”
From Candida auris skin tropism and antifungal resistance are mediated by carbonic anhydrase Nce103 (2025) · cites this paper as [34]
In C. neoformans, brain glucose induces AmB tolerance without affecting the MIC, mediated by Mig1 and involving inhibition of ergosterol synthesis and promotion of competing compounds.
“Similarly, in C. neoformans, brain glucose has been shown to induce AmB tolerance without affecting the MIC. This process is mediated by the zinc-finger transcription factor Mig1 and involves more complex mechanisms, such as the inhibition of ergosterol synthesis and the promotion of competing compounds that contribute to antifungal tolerance [116].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [116]
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References 55 · Cited by 46
- Authors
- Chen, L., Tian, X., Zhang, L., Wang, W., Hu, P., Ma, Z., Li, Y., Li, S., Shen, Z., Fan, X., Ye, L., Ke, W., Wu, Y., Shui, G., Xiao, M., He, G.-J., Yang, Y., Fang, W., Bai, F., Liao, G., Chen, M., Lin, X., Li, C., & Wang, L.
- Affiliations
- Chinese Academy of Sciences (CN)
- Southwest University (CN)
- University of Georgia (US)
- Capital Medical University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Beijing Radiation Center (CN)
- Guangxi Academy of Sciences (CN)
- Peking University (CN)
- Second Military Medical University (CN)
- Corresponding author
- Wang, Linqi
- ORCID
- Venue
- Nature Microbiology
- Published
- 2024-01-15
- Volume
- 9
- Issue
- 2
- Pages
- 346-358
- ISSN
- 2058-5276 (ISSN-L)
- OpenAlex
- W4390876171
- Semantic Scholar
- fde9dc5eb325497be86725a2660a716e93617a45
- Cited by
- 46
- References
- 55
- Citations by year
- 2026: 17 · 2025: 19 · 2024: 10
- FWCI
- 14.05
- Type
- journal article
- Language
- en
- Open access
- green
- dx.doi.org
- Licence
- Locations
- Nature Microbiology (publishedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (32100153, 82073789, 82172291, 31970077)
- National Key Research and Development Program of China (2022YFC2303000, 2021YFA0911300, 2021YFC2100600)
- Topics
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- Cryptococcus neoformans, cryptococcal meningitis, amphotericin B, fungicide tolerance, brain glucose, Mig1, glucose repression, ergosterol biosynthesis, inositol phosphorylceramide, aureobasidin A, host-pathogen interaction, cerebrospinal fluid, antifungal resistance
- MeSH terms
- Amphotericin B, Animals, Antifungal Agents, Brain, Cryptococcus neoformans, Ergosterol, Humans, Meningitis, Cryptococcal, Mice
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