title: Nitazoxanide Disrupts Membrane Potential and Intrabacterial pH Homeostasis of Mycobacterium tuberculosis.
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.
authors.affiliation: Departments of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Ave, New York, NY 10065.
authors.forename: Luiz Pedro S
authors.initials: LP
authors.lastname: de Carvalho
authors.forename: Crystal M
authors.initials: CM
authors.lastname: Darby
authors.forename: Kyu Y
authors.initials: KY
authors.lastname: Rhee
authors.forename: Carl
authors.initials: C
authors.lastname: Nathan
references.citation: Tuber Lung Dis. 1999;79(5):319-20
references.pmid: 10707260
references.citation: Antimicrob Agents Chemother. 2000 Sep;44(9):2254-8
references.pmid: 10952564
references.citation: J Chromatogr A. 2008 Sep 12;1204(1):48-55
references.pmid: 18701108
references.citation: Science. 2009 May 8;324(5928):801-4
references.pmid: 19299584
references.citation: Nature. 1998 Jul 9;394(6689):192-5
references.pmid: 9671304
references.citation: J Antimicrob Chemother. 2002 Jan;49(1):103-11
references.pmid: 11751773
references.citation: Nature. 2011 Jan 27;469(7331):483-90
references.pmid: 21270886
references.citation: Nat Rev Microbiol. 2011 Jan;9(1):62-75
references.pmid: 21164535
references.citation: Adv Microb Physiol. 2009;55:1-79, 317
references.pmid: 19573695
references.citation: Chem Biol. 2010 Oct 29;17(10):1122-31
references.pmid: 21035735
references.citation: Antimicrob Agents Chemother. 1998 Nov;42(11):2836-40
references.pmid: 9797212
references.citation: Science. 2009 Feb 27;323(5918):1215-8
references.pmid: 19251630
references.citation: Tuberculosis (Edinb). 2008 Aug;88 Suppl 1:S25-33
references.pmid: 18762150
references.citation: J Bacteriol. 2009 Aug;191(15):4714-21
references.pmid: 19465648
references.citation: Nat Rev Microbiol. 2011 May;9(5):330-43
references.pmid: 21464825
references.citation: Antimicrob Agents Chemother. 2007 Mar;51(3):868-76
references.pmid: 17158936
references.citation: Antimicrob Agents Chemother. 2008 Nov;52(11):4069-71
references.pmid: 18710916
references.citation: Nat Med. 2008 Aug;14(8):849-54
references.pmid: 18641659
references.citation: Front Biosci. 2004 May 01;9:1059-72
references.pmid: 14977529
references.citation: Science. 2005 Jan 14;307(5707):223-7
references.pmid: 15591164
references.citation: Nature. 1969 Mar 15;221(5185):1016-8
references.pmid: 4180173
references.citation: Aliment Pharmacol Ther. 2006 Sep 1;24(5):887-94
references.pmid: 16918894
references.citation: Antimicrob Agents Chemother. 1996 Oct;40(10):2266-70
references.pmid: 8891127
references.citation: Chem Biol. 2010 Apr 23;17(4):323-32
references.pmid: 20416504
references.citation: J Med Chem. 2009 Apr 9;52(7):2109-18
references.pmid: 19271749
references.citation: Antimicrob Agents Chemother. 1998 Aug;42(8):1959-65
references.pmid: 9687390
references.citation: J Med Chem. 2009 Oct 8;52(19):5789-92
references.pmid: 19736929
references.citation: Gastroenterology. 2009 Mar;136(3):856-62
references.pmid: 19135998
references.citation: Antiviral Res. 2008 Jan;77(1):56-63
references.pmid: 17888524
references.citation: Antimicrob Agents Chemother. 2006 Mar;50(3):1112-7
references.pmid: 16495282
references.citation: Nature. 2000 Jun 22;405(6789):962-6
references.pmid: 10879539