2. Academic Validation
  3. A dual action small molecule enhances azoles and overcomes resistance through co-targeting Pdr5 and Vma1

A dual action small molecule enhances azoles and overcomes resistance through co-targeting Pdr5 and Vma1

  • Transl Res. 2022 Sep;247:39-57. doi: 10.1016/j.trsl.2022.04.002.
Ning-Ning Liu 1,  Jia Zhou 2,  Tong Jiang 3,  Maureen Tarsio 4,  Feifei Yu 5,  Xuehan Zheng 6,  Wanjun Qi 7,  Lin Liu 2,  Jing-Cong Tan 2,  Luqi Wei 2,  Jun Ding 8,  Jingquan Li 2,  Lingbing Zeng 9,  Biao Ren 10,  Xiaotian Huang 11,  Yibing Peng 12,  Yong-Bing Cao 13,  Yanbin Zhao 14,  Xin-Yu Zhang 15,  Patricia M Kane 4,  Changbin Chen 16,  Hui Wang 17
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected].
  • 2 State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3 The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China.
  • 4 Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA.
  • 5 Institute of Environmental Pollution and Health, School of Environmental and Chemical Engineering, Shanghai University, Shanghai, China.
  • 6 School of Environmental Science and Engineering, Shanghai Jiao Tong University, Shanghai, China.
  • 7 Division of Infectious Diseases, Boston Children's Hospital/Harvard Medical School, Boston, MA, USA.
  • 8 Computational biology department, Carnegie Mellon University, Pittsburgh, PA, USA.
  • 9 Department of Laboratory Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
  • 10 State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, Sichuan University, Chengdu, Sichuan, China.
  • 11 Department of Medical Microbiology, School of Medicine, Nanchang University, Nanchang, Jiangxi, China.
  • 12 Department of Laboratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Faculty of Medical Laboratory Science, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 13 Department of Vascular Disease, Shanghai TCM-Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China; Shanghai TCM-Integrated Institute of Vascular Disease, Shanghai, China.
  • 14 School of Environmental Science and Engineering, Shanghai Jiao Tong University, Shanghai, China; Shanghai Institute of Pollution Control and Ecological Security, Shanghai, China.
  • 15 School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 16 The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China. Electronic address: [email protected].
  • 17 State Key Laboratory of Oncogenes and Related Genes, Center for Single-Cell Omics, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: [email protected].
PMID: 35452875 DOI: 10.1016/j.trsl.2022.04.002
Abstract

Fungal Infection threatens human health worldwide due to the limited arsenal of antifungals and the rapid emergence of resistance. Epidermal growth factor receptor (EGFR) is demonstrated to mediate epithelial cell endocytosis of the leading human Fungal pathogen, Candida albicans. However, whether EGFR inhibitors act on Fungal cells remains unknown. Here, we discovered that the specific EGFR inhibitor osimertinib mesylate (OSI) potentiates azole efficacy against diverse Fungal pathogens and overcomes azole resistance. Mechanistic investigation revealed a conserved activity of OSI by promoting intracellular fluconazole accumulation via inhibiting Pdr5 and disrupting V-ATPase function via targeting Vma1 at serine 274, eventually leading to inactivation of the global regulator TOR. Evaluation of the in vivo efficacy and toxicity of OSI demonstrated its potential clinical application in impeding fluconazole resistance. Thus, the identification of OSI as a dual action Antifungal with co-targeting activity proposes a potentially effective therapeutic strategy to treat life-threatening fungal Infection and overcome Antifungal resistance.

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