Auranofin and N-heterocyclic carbene gold-analogs are potent inhibitors of the bacteria Helicobacter pylori.
Auranofin is an FDA-approved gold-containing compound used for the treatment of rheumatoid arthritis. Recent reports of antimicrobial activity against protozoa and bacteria indicate that auranofin targets the reductive enzyme thioredoxin reductase (TrxR). We evaluated auranofin as well as five auranofin analogs containing N-heterocyclic carbenes (instead of the triethylphosphane present in auranofin) and five gold-carbene controls for their ability to inhibit or kill Helicobacter pylori in vitro Auranofin completely inhibited bacterial growth at 1.2 μM. Purified H. pylori TrxR was inhibited by auranofin in a cell-free assay (IC50 ∼88 nM). The most active gold(I)-N-heterocyclic carbene compounds exhibited MICs comparable to auranofin against H. pylori (2 μM), while also exhibiting lower toxicities for human embryonic kidney cells (HEK-293T cells). Median toxic concentrations (TC50) were 13-20-fold higher compared to auranofin indicating that they were less cytotoxic. The N-heterocyclic carbene analogs maybe well tolerated, but further evaluation is needed in vivo Finally, auranofin was synergistic with the antibiotic amoxicillin, suggesting that targeting both the reductive enzyme TrxR and cell wall synthesis may be effective against H. pylori infections.
Department of Pediatrics, 1760 Haygood, Emory University, Atlanta, GA 30022, USA.
Joshua P
JP
Owings
Department of Pediatrics, 1760 Haygood, Emory University, Atlanta, GA 30022, USA Department of Medical Research, Atlanta VA Medical Center, 1670 Clairmont Rd, Decatur, GA 30033, USA.
Nina N
NN
McNair
Department of Chemistry, Brooklyn College and The Graduate Center, The City University of New York, Brooklyn, NY 11210, USA Chemistry and Biology PhD Programs, The Graduate Center, The City University of New York, 365 Fifth Avenue, New York, NY 10016, USA.
Yiu Fung
YF
Mui
Department of Medical Biochemistry, and Biophysics, Karolinska Institute, SE 171 77 Stockholm, Sweden.
Tomas N
TN
Gustafsson
Department of Medical Biochemistry, and Biophysics, Karolinska Institute, SE 171 77 Stockholm, Sweden.
Arne
A
Holmgren
Department of Chemistry, Brooklyn College and The Graduate Center, The City University of New York, Brooklyn, NY 11210, USA Chemistry and Biology PhD Programs, The Graduate Center, The City University of New York, 365 Fifth Avenue, New York, NY 10016, USA.
Maria
M
Contel
Department of Pediatrics, 1760 Haygood, Emory University, Atlanta, GA 30022, USA.
Joanna B
JB
Goldberg
Department of Pediatrics, 1760 Haygood, Emory University, Atlanta, GA 30022, USA Department of Medical Research, Atlanta VA Medical Center, 1670 Clairmont Rd, Decatur, GA 30033, USA jmead@emory.edu.
Jan R
JR
Mead
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001310:Auranofin / Q000737:chemistry / Q000494:pharmacology*; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D016480:Helicobacter pylori / Q000187:drug effects*; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008697:Methane / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D050607:Organogold Compounds / Q000737:chemistry / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D006571:Heterocyclic Compounds; D050607:Organogold Compounds; C030011:carbene; D001310:Auranofin; D008697:Methane
Helicobacter pylori; antibacterial agents; auranofin; drug therapy; gold(I)-N-heterocyclic carbenes, antibiotic resistance; thioredoxin reductase