Open AccessNitazoxanide Disrupts Membrane Potential and Intrabacterial pH Homeostasis of Mycobacterium tuberculosis
Author(s) -
Luiz Pedro S. de Carvalho,
Crystal M. Darby,
Kyu Y. Rhee,
Carl Nathan
Publication year - 2011
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/ml200157f
Subject(s) - nitazoxanide , mycobacterium tuberculosis , niclosamide , indoleamine 2,3 dioxygenase , microbiology and biotechnology , antiparasitic agent , tuberculosis , chemistry , mode of action , pharmacology , biology , medicine , biochemistry , immunology , tryptophan , ecology , amino acid , pathology
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.