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Nitazoxanide Disrupts Membrane Potential and Intrabacterial pH Homeostasis of Mycobacterium tuberculosis.

TitleNitazoxanide Disrupts Membrane Potential and Intrabacterial pH Homeostasis of Mycobacterium tuberculosis.
Publication TypeJournal Article
Year of Publication2011
Authorsde Carvalho LPedro S, Darby CM, Rhee KY, Nathan C
JournalACS Med Chem Lett
Volume2
Issue11
Pagination849-854
Date Published2011
ISSN1948-5875
Abstract

Nitazoxanide (Alinia(®)), a nitro-thiazolyl antiparasitic drug, kills diverse microorganisms by unknown mechanisms. Here we identified two actions of nitazoxanide against Mycobacterium tuberculosis (Mtb): disruption of Mtb's membrane potential and pH homeostasis. Both actions were shared by a structurally related anti-mycobacterial compound, niclosamide. Reactive nitrogen intermediates were reported to synergize with nitazoxanide and its deacetylated derivative tizoxanide in killing Mtb. Herein, however, we could not attribute this to increased uptake of nitazoxanide or tizoxanide as monitored by targeted metabolomics, nor to increased impact of nitazoxanide on Mtb's membrane potential or intrabacterial pH. Thus, further mechanisms of action of nitazoxanide or tizoxanide may await discovery. The multiple mechanisms of action may contribute to Mtb's ultra-low frequency of resistance against nitazoxanide.

DOI10.1021/ml200157f
Alternate JournalACS Med Chem Lett
PubMed ID22096616
PubMed Central IDPMC3215101
Grant ListR01 AI081725 / AI / NIAID NIH HHS / United States
R01 AI081725-01 / AI / NIAID NIH HHS / United States
R21 AI081094 / AI / NIAID NIH HHS / United States
R21 AI081094-01A1 / AI / NIAID NIH HHS / United States

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