IRISH SOCIETY OF GASTROENTEROLOGY 2021
Best Scientific Abstract 2021 - Second Prize
Dr Thomas J Butler
School of Medicine, Trinity College Dublin
In silico and in vitro Screening to Identify Lead Hit Compounds Targeting The Key Survival Purine Nucleoside Phosphorylase (PNP) Enzyme of Helicobacter pylori
T. J. Butler , S. Taher , S. Smith [1,2]
 Dept. of Clinical Medicine, School of Medicine, Trinity College Dublin.  School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin.
Resistance to many of the antibiotics used to treat Helicobacter pylori (HP) infection is on the rise. Indeed, the WHO has included H. pylori on their priority list of antibiotic-resistant bacteria to guide research and development into novel antimicrobials. To this end, a virtual screen (VS) of 550k+ compounds was carried out against the purine nucleoside phosphorylase enzyme (PNP), a key survival enzyme of HP.
(i) To perform in silico VS to identify new compounds with potential activity against the HP PNP enzyme, (ii) and to test the in vitro antimicrobial activity of the identified compounds.
Using mixed cheminformatics and structural approaches, computational tools were deployed to identify several lead-hits to carry forward to in vitro screening. Lead-hits were tested for antimicrobial efficacy against reference strains (J99 and ATCC60190) and clinical isolates of HP using a broth microdilution approach. Clarithromycin was used as a positive control. Selectivity was established using a viability assay with a stomach epithelial cell line AGS.
5 lead-hits were selected from VS and tested in vitro. All compounds showed antimicrobial activity against the reference strains and both clarithromycin-sensitive and clarithromycin-resistant clinical isolates of HP (MIC50 4.9 – 51 µg/mL). 4 compounds had no effect on the viability of human cells showing selective antimicrobial activity against H. pylori.
VS provided a cost-efficient method to identify, selective antimicrobial agents for H. pylori resulting in the identification of several lead targets that may be further developed to increase selectivity and potency.