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Clionamines stimulate autophagy, inhibit Mycobacterium tuberculosis survival in macrophages, and target Pik1.
Persaud, Rosanne; Li, Sheena C; Chao, Joseph D; Forestieri, Roberto; Donohue, Elizabeth; Balgi, Aruna D; Zheng, Xingji; Chao, Jesse T; Yashiroda, Yoko; Yoshimura, Mami; Loewen, Christopher J R; Gingras, Anne-Claude; Boone, Charles; Av-Gay, Yossef; Roberge, Michel; Andersen, Raymond J.
Affiliation
  • Persaud R; Departments of Chemistry and Earth Ocean & Atmospheric Sciences, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada.
  • Li SC; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada; RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama, Japan.
  • Chao JD; Division of Infectious Disease, Departments of Medicine and Microbiology and immunology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
  • Forestieri R; Departments of Chemistry and Earth Ocean & Atmospheric Sciences, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada.
  • Donohue E; Deptartment of Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
  • Balgi AD; Deptartment of Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
  • Zheng X; Division of Infectious Disease, Departments of Medicine and Microbiology and immunology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
  • Chao JT; Department of Cellular and Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
  • Yashiroda Y; RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama, Japan.
  • Yoshimura M; RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama, Japan.
  • Loewen CJR; Department of Cellular and Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
  • Gingras AC; Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.
  • Boone C; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, 160 College Street, Toronto, ON M5S 3E1, Canada; RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako,
  • Av-Gay Y; Division of Infectious Disease, Departments of Medicine and Microbiology and immunology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada. Electronic address: yossi@mail.ubc.ca.
  • Roberge M; Deptartment of Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada. Electronic address: michelr@mail.ubc.ca.
  • Andersen RJ; Departments of Chemistry and Earth Ocean & Atmospheric Sciences, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada. Electronic address: raymond.andersen@ubc.ca.
Cell Chem Biol ; 29(5): 870-882.e11, 2022 05 19.
Article in En | MEDLINE | ID: mdl-34520745
ABSTRACT
The pathogen Mycobacterium tuberculosis (Mtb) evades the innate immune system by interfering with autophagy and phagosomal maturation in macrophages, and, as a result, small molecule stimulation of autophagy represents a host-directed therapeutics (HDTs) approach for treatment of tuberculosis (TB). Here we show the marine natural product clionamines activate autophagy and inhibit Mtb survival in macrophages. A yeast chemical-genetics approach identified Pik1 as target protein of the clionamines. Biotinylated clionamine B pulled down Pik1 from yeast cell lysates and a clionamine analog inhibited phosphatidyl 4-phosphate (PI4P) production in yeast Golgi membranes. Chemical-genetic profiles of clionamines and cationic amphiphilic drugs (CADs) are closely related, linking the clionamine mode of action to co-localization with PI4P in a vesicular compartment. Small interfering RNA (siRNA) knockdown of PI4KB, a human homolog of Pik1, inhibited the survival of Mtb in macrophages, identifying PI4KB as an unexploited molecular target for efforts to develop HDT drugs for treatment of TB.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Tuberculosis / Saccharomyces cerevisiae Proteins / Mycobacterium tuberculosis Limits: Humans Language: En Journal: Cell Chem Biol Year: 2022 Document type: Article Affiliation country:
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Tuberculosis / Saccharomyces cerevisiae Proteins / Mycobacterium tuberculosis Limits: Humans Language: En Journal: Cell Chem Biol Year: 2022 Document type: Article Affiliation country: