Clionamines stimulate autophagy, inhibit Mycobacterium tuberculosis survival in macrophages, and target Pik1

Rosanne Persaud; Sheena C Li; Joseph D Chao; Roberto Forestieri; Elizabeth Donohue; Aruna D Balgi; Xingji Zheng; Jesse T Chao; Yoko Yashiroda; Mami Yoshimura; Christopher J R Loewen; Anne-Claude Gingras; Charles Boone; Yossef Av-Gay; Michel Roberge; Raymond J Andersen

doi:10.1016/j.chembiol.2021.07.017

Clionamines stimulate autophagy, inhibit Mycobacterium tuberculosis survival in macrophages, and target Pik1

Cell Chem Biol. 2022 May 19;29(5):870-882.e11. doi: 10.1016/j.chembiol.2021.07.017. Epub 2021 Sep 13.

Authors

Rosanne Persaud¹, Sheena C Li², Joseph D Chao³, Roberto Forestieri¹, Elizabeth Donohue⁴, Aruna D Balgi⁴, Xingji Zheng³, Jesse T Chao⁵, Yoko Yashiroda⁶, Mami Yoshimura⁶, Christopher J R Loewen⁵, Anne-Claude Gingras⁷, Charles Boone⁸, Yossef Av-Gay⁹, Michel Roberge¹⁰, Raymond J Andersen¹¹

Affiliations

¹ Departments of Chemistry and Earth Ocean & Atmospheric Sciences, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada.
² 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.
³ Division of Infectious Disease, Departments of Medicine and Microbiology and immunology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
⁴ Deptartment of Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
⁵ Department of Cellular and Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.
⁶ RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama, Japan.
⁷ Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital, 600 University Avenue, Toronto, ON M5G 1X5, Canada.
⁸ 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, Saitama, Japan. Electronic address: charlie.boone@utoronto.ca.
⁹ 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.
¹⁰ 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.
¹¹ 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.

PMID: 34520745
DOI: 10.1016/j.chembiol.2021.07.017

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.

Keywords: PI4KB; autophagy; host-directed therapeutics; macrophages; marine natural product; pik1; tuberculosis; xenophagy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

1-Phosphatidylinositol 4-Kinase / metabolism
Autophagy
Humans
Macrophages / metabolism
Mycobacterium tuberculosis*
Saccharomyces cerevisiae
Saccharomyces cerevisiae Proteins* / metabolism
Tuberculosis* / drug therapy

Substances

Saccharomyces cerevisiae Proteins
1-Phosphatidylinositol 4-Kinase
PIK1 protein, S cerevisiae

Abstract

Publication types

MeSH terms

Substances

Grants and funding