title: In vitro and in vivo activities of HPi1, a selective antimicrobial against Helicobacter pylori.
abstract: A high-throughput screen (HTS) was performed to identify molecules specifically active against Helicobacter pylori, the causative agent of peptic ulcer and gastric carcinoma. Currently, treatment of H. pylori infection is suboptimal, with failure rates approaching 25%, despite triple therapy with two broad-spectrum antibiotics and a proton pump inhibitor or quadruple therapy with added bismuth. The HTS was performed in 384-well plates, and reduction of the metabolic indicator resazurin was used as a reporter for cell growth. Diverse molecules from commercial sources were identified as hits, and in vitro validations included measurements of MIC and time-dependent killing as well as anaerobic susceptibility testing against a panel of gut microbes. In vivo validation included testing in the mouse model of H. pylori infection. The small molecule HPi1 (3-hydrazinoquinoxaline-2-thiol) had excellent potency, with an MIC of 0.08 to 0.16 μg/ml and good selectivity for H. pylori compared to a panel of commensal bacteria. HPi1 was also effective in a mouse model of H. pylori infection, reducing colony counts to below the limit of detection after oral dosing of 25 mg/kg/day for 3 days. HPi1 is a promising lead in the search for more effective and specific H. pylori therapeutics.
authors.affiliation: Arietis Pharma, Boston, Massachusetts, USA.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Gavrish
authors.affiliation: Arietis Pharma, Boston, Massachusetts, USA.
authors.forename: Binu
authors.initials: B
authors.lastname: Shrestha
authors.affiliation: Antimicrobial Discovery Center and Department of Biology, Northeastern University, Boston, Massachusetts, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Chen
authors.affiliation: Arietis Pharma, Boston, Massachusetts, USA.
authors.forename: Ida
authors.initials: I
authors.lastname: Lister
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: E Jeffrey
authors.initials: EJ
authors.lastname: North
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Lee
authors.affiliation: Arietis Pharma, Boston, Massachusetts, USA.
authors.forename: Angel
authors.initials: A
authors.lastname: Han
authors.affiliation: Arietis Pharma, Boston, Massachusetts, USA.
authors.forename: Bronwyn
authors.initials: B
authors.lastname: Williams
authors.affiliation: Arietis Pharma, Boston, Massachusetts, USA.
authors.forename: David
authors.initials: D
authors.lastname: Charnuska
authors.affiliation: Arietis Pharma, Boston, Massachusetts, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Coleman
authors.affiliation: Antimicrobial Discovery Center and Department of Biology, Northeastern University, Boston, Massachusetts, USA.
authors.forename: Kim
authors.initials: K
authors.lastname: Lewis
authors.affiliation: Arietis Pharma, Boston, Massachusetts, USA Antimicrobial Discovery Center and Department of Biology, Northeastern University, Boston, Massachusetts, USA m.lafleur@arietiscorp.com.
authors.forename: Michael D
authors.initials: MD
authors.lastname: LaFleur
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D016481:Helicobacter Infections / Q000188:drug therapy / Q000382:microbiology; D016480:Helicobacter pylori / Q000187:drug effects*; D057166:High-Throughput Screening Assays; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D010078:Oxazines; D011479:Protamines / Q000493:pharmacokinetics / Q000494:pharmacology*; D014966:Xanthenes
chemical_list: D000900:Anti-Bacterial Agents; D010078:Oxazines; D011479:Protamines; D014966:Xanthenes; C068621:protamine 2; C005843:resazurin