2. Academic Validation
  3. Brain glucose induces tolerance of Cryptococcus neoformans to amphotericin B during meningitis

Brain glucose induces tolerance of Cryptococcus neoformans to amphotericin B during meningitis

  • Nat Microbiol. 2024 Jan 15. doi: 10.1038/s41564-023-01561-1.
Lei Chen # 1,  Xiuyun Tian # 1,  Lanyue Zhang # 1 2,  Wenzhao Wang 1,  Pengjie Hu 1,  Zhongyi Ma 3,  Yeqi Li 4,  Shibin Li 1,  Zhenghao Shen 1 2,  Xin Fan 5,  Leixin Ye 3,  Weixin Ke 1,  Yao Wu 6,  Guanghou Shui 7,  Meng Xiao 8 9,  Guang-Jun He 1,  Ying Yang 10,  Wenxia Fang 11,  Fan Bai 12,  Guojian Liao 3,  Min Chen 13,  Xiaorong Lin 4,  Chong Li 3,  Linqi Wang 14 15
Affiliations

Affiliations

  • 1 State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
  • 2 University of Chinese Academy of Sciences, Beijing, China.
  • 3 Medical Research Institute, College of Pharmaceutical Sciences, Southwest University, Chongqing, China.
  • 4 Department of Microbiology, University of Georgia, Athens, GA, USA.
  • 5 Department of Infectious Diseases and Clinical Microbiology, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
  • 6 State Key Laboratory of Plant Genomics, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
  • 7 State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
  • 8 Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.
  • 9 Beijing Key Laboratory for Mechanisms Research and Precision Diagnosis of Invasive Fungal Diseases, Beijing, China.
  • 10 Beijing Key Laboratory of New Molecular Diagnosis Technologies for Infectious Disease, Department of Biotechnology, Beijing Institute of Radiation Medicine, Beijing, China.
  • 11 Institute of Biological Science and Technology, Guangxi Academy of Sciences, Nanning, Guangxi, China.
  • 12 Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences, Peking University, Beijing, China.
  • 13 Department of Dermatology, Shanghai Key Laboratory of Medical Mycology, Changzheng Hospital, Naval Medical University, Shanghai, China.
  • 14 State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China. [email protected].
  • 15 University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 38225460 DOI: 10.1038/s41564-023-01561-1
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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