title: Nitazoxanide stimulates autophagy and inhibits mTORC1 signaling and intracellular proliferation of Mycobacterium tuberculosis.
abstract: Tuberculosis, caused by Mycobacterium tuberculosis infection, is a major cause of morbidity and mortality in the world today. M. tuberculosis hijacks the phagosome-lysosome trafficking pathway to escape clearance from infected macrophages. There is increasing evidence that manipulation of autophagy, a regulated catabolic trafficking pathway, can enhance killing of M. tuberculosis. Therefore, pharmacological agents that induce autophagy could be important in combating tuberculosis. We report that the antiprotozoal drug nitazoxanide and its active metabolite tizoxanide strongly stimulate autophagy and inhibit signaling by mTORC1, a major negative regulator of autophagy. Analysis of 16 nitazoxanide analogues reveals similar strict structural requirements for activity in autophagosome induction, EGFP-LC3 processing and mTORC1 inhibition. Nitazoxanide can inhibit M. tuberculosis proliferation in vitro. Here we show that it inhibits M. tuberculosis proliferation more potently in infected human THP-1 cells and peripheral monocytes. We identify the human quinone oxidoreductase NQO1 as a nitazoxanide target and propose, based on experiments with cells expressing NQO1 or not, that NQO1 inhibition is partly responsible for mTORC1 inhibition and enhanced autophagy. The dual action of nitazoxanide on both the bacterium and the host cell response to infection may lead to improved tuberculosis treatment.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Karen K Y
authors.initials: KK
authors.lastname: Lam
authors.forename: Xingji
authors.initials: X
authors.lastname: Zheng
authors.forename: Roberto
authors.initials: R
authors.lastname: Forestieri
authors.forename: Aruna D
authors.initials: AD
authors.lastname: Balgi
authors.forename: Matt
authors.initials: M
authors.lastname: Nodwell
authors.forename: Sarah
authors.initials: S
authors.lastname: Vollett
authors.forename: Hilary J
authors.initials: HJ
authors.lastname: Anderson
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Andersen
authors.forename: Yossef
authors.initials: Y
authors.lastname: Av-Gay
authors.forename: Michel
authors.initials: M
authors.lastname: Roberge
mesh_terms: D000977:Antiparasitic Agents / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D009000:Monocytes / Q000382:microbiology; D046912:Multiprotein Complexes; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000254:growth & development*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000037:antagonists & inhibitors; D009574:Nitro Compounds; D010588:Phagosomes / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases; D013844:Thiazoles / Q000494:pharmacology*; D014376:Tuberculosis / Q000188:drug therapy / Q000517:prevention & control
chemical_list: D000977:Antiparasitic Agents; D046912:Multiprotein Complexes; D009574:Nitro Compounds; D011506:Proteins; D013844:Thiazoles; C104067:tizoxanide; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; C041747:nitazoxanide