title: A reprofiled drug, auranofin, is effective against metronidazole-resistant Giardia lamblia.
abstract: Giardiasis is one of the most common causes of diarrheal disease worldwide. Treatment is primarily with 5-nitro antimicrobials, particularly metronidazole. Resistance to metronidazole has been described, and treatment failures can occur in up to 20% of cases, making development of alternative antigiardials an important goal. To this end, we have screened a chemical library of 746 approved human drugs and 164 additional bioactive compounds for activity against Giardia lamblia. We identified 56 compounds that caused significant inhibition of G. lamblia growth and attachment. Of these, 15 were previously reported to have antigiardial activity, 20 were bioactive but not approved for human use, and 21 were drugs approved for human use for other indications. One notable compound of the last group was the antirheumatic drug auranofin. Further testing revealed that auranofin was active in the low (4 to 6)-micromolar range against a range of divergent G. lamblia isolates representing both human-pathogenic assemblages A and B. Most importantly, auranofin was active against multiple metronidazole-resistant strains. Mechanistically, auranofin blocked the activity of giardial thioredoxin oxidoreductase, a critical enzyme involved in maintaining normal protein function and combating oxidative damage, suggesting that this inhibition contributes to the antigiardial activity. Furthermore, auranofin was efficacious in vivo, as it eradicated infection with different G. lamblia isolates in different rodent models. These results indicate that the approved human drug auranofin could be developed as a novel agent in the armamentarium of antigiardial drugs, particularly against metronidazole-resistant strains.
authors: Department of Medicine, University of California, San Diego, La Jolla, California, USA.
authors: Noa
authors: N
authors: Tejman-Yarden
authors: Yukiko
authors: Y
authors: Miyamoto
authors: David
authors: D
authors: Leitsch
authors: Jennifer
authors: J
authors: Santini
authors: Anjan
authors: A
authors: Debnath
authors: Jiri
authors: J
authors: Gut
authors: James H
authors: JH
authors: McKerrow
authors: Sharon L
authors: SL
authors: Reed
authors: Lars
authors: L
authors: Eckmann
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology*; D018501:Antirheumatic Agents / Q000737:chemistry / Q000494:pharmacology; D001310:Auranofin / Q000737:chemistry / Q000494:pharmacology*; D058492:Drug Repositioning; D004351:Drug Resistance / Q000187:drug effects; D004403:Dysentery / Q000188:drug therapy* / Q000469:parasitology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005849:Gerbillinae; D016829:Giardia lamblia / Q000187:drug effects* / Q000502:physiology; D005873:Giardiasis / Q000188:drug therapy* / Q000469:parasitology; D057166:High-Throughput Screening Assays; D006801:Humans; D008795:Metronidazole / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D018384:Oxidative Stress; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013879:Thioredoxins / Q000378:metabolism
chemical_list: D000890:Anti-Infective Agents; D018501:Antirheumatic Agents; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D008795:Metronidazole; D001310:Auranofin; D013879:Thioredoxins; D010088:Oxidoreductases
references: Mol Biochem Parasitol. 2010 May;171(1):17-24
references: 20093143
references: Antimicrob Agents Chemother. 2011 Oct;55(10):4643-51
references: 21825286
references: J Biol Inorg Chem. 2009 May;14(4):507-19
references: 19165513
references: Scand J Rheumatol Suppl. 1986;63:19-28
references: 3110942
references: Antimicrob Agents Chemother. 1998 Jun;42(6):1488-92
references: 9624499
references: J Microbiol Methods. 2011 Mar;84(3):398-405
references: 21262276
references: Trends Parasitol. 2006 May;22(5):203-8
references: 16545611
references: Cell Mol Life Sci. 2009 Dec;66(23):3821-6
references: 19701717
references: Trans R Soc Trop Med Hyg. 1992 Sep-Oct;86(5):521-2
references: 1475822
references: J Biol Chem. 1998 Aug 7;273(32):20096-101
references: 9685351
references: Int J Antimicrob Agents. 2010 Jul;36(1):37-42
references: 20456926
references: Nucleic Acids Res. 2006;34(14):4012-24
references: 16914442
references: J Med Chem. 2009 Jul 9;52(13):4038-53
references: 19480409
references: Parasitol Today. 1988 Nov;4(11):322
references: 15463019
references: Anaesth Intensive Care. 2008 Jul;36(4):502-12
references: 18714617
references: Expert Opin Drug Saf. 2003 Nov;2(6):529-41
references: 14585063
references: Mol Cell Biochem. 2004 Oct;265(1-2):151-60
references: 15543945
references: Phytother Res. 2003 Jun;17(6):681-2
references: 12820241
references: PLoS Med. 2007 Jun;4(6):e206
references: 17579510
references: Toxicol Lett. 2008 Nov 10;182(1-3):1-6
references: 18812216
references: Antimicrob Agents Chemother. 2011 Feb;55(2):667-75
references: 21078930
references: J Nat Prod. 2000 Oct;63(10):1414-6
references: 11076565
references: Parasitol Res. 2010 Jul;107(2):487-93
references: 20495929
references: Inflammopharmacology. 2008 Jun;16(3):112-25
references: 18523733
references: J Infect Dis. 1990 Dec;162(6):1408-11
references: 2230276
references: Br J Rheumatol. 1997 May;36(5):560-72
references: 9189058
references: Mol Biochem Parasitol. 1998 Apr 1;92(1):59-69
references: 9574910
references: J Antimicrob Chemother. 2010 Dec;65(12):2598-601
references: 20861141
references: Antimicrob Agents Chemother. 1993 Feb;37(2):328-31
references: 8452365
references: Gut. 2012 Feb;61(2):214-9
references: 21911849
references: Clin Microbiol Rev. 2001 Jan;14(1):150-64
references: 11148007
references: J Biol Chem. 2009 Oct 16;284(42):28977-85
references: 19710012
references: Clin Microbiol Rev. 2001 Jan;14(1):114-28
references: 11148005
references: Acta Trop. 1995 Sep;60(1):35-46
references: 8546037
references: J Antimicrob Chemother. 2011 Aug;66(8):1756-65
references: 21602576
references: J Antimicrob Chemother. 2011 Jul;66(7):1533-6
references: 21486854
references: Nat Med. 2012 Jun;18(6):956-60
references: 22610278
references: Int J Parasitol. 1998 Jan;28(1):149-64
references: 9504342
references: Expert Opin Pharmacother. 2007 Aug;8(12):1885-902
references: 17696791
references: Am J Infect Control. 2005 Feb;33(1):15-22
references: 15685130
references: J Antimicrob Chemother. 1987 Oct;20(4):519-22
references: 3500164
references: Crit Rev Food Sci Nutr. 1998 Aug;38(6):421-64
references: 9759559