Cargando…
Targeting the Essential Transcription Factor HP1043 of Helicobacter pylori: A Drug Repositioning Study
Antibiotic-resistant bacterial pathogens are a very challenging problem nowadays. Helicobacter pylori is one of the most widespread and successful human pathogens since it colonizes half of the world population causing chronic and atrophic gastritis, peptic ulcer, mucosa-associated lymphoid tissue-l...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9135449/ https://www.ncbi.nlm.nih.gov/pubmed/35647033 http://dx.doi.org/10.3389/fmolb.2022.887564 |
_version_ | 1784713961732571136 |
---|---|
author | Antoniciello, Federico Roncarati, Davide Zannoni, Annamaria Chiti, Elena Scarlato, Vincenzo Chiappori, Federica |
author_facet | Antoniciello, Federico Roncarati, Davide Zannoni, Annamaria Chiti, Elena Scarlato, Vincenzo Chiappori, Federica |
author_sort | Antoniciello, Federico |
collection | PubMed |
description | Antibiotic-resistant bacterial pathogens are a very challenging problem nowadays. Helicobacter pylori is one of the most widespread and successful human pathogens since it colonizes half of the world population causing chronic and atrophic gastritis, peptic ulcer, mucosa-associated lymphoid tissue-lymphoma, and even gastric adenocarcinoma. Moreover, it displays resistance to numerous antibiotics. One of the H. pylori pivotal transcription factors, HP1043, plays a fundamental role in regulating essential cellular processes. Like other bacterial transcription factors, HP1043 does not display a eukaryote homolog. These characteristics make HP1043 a promising candidate to develop novel antibacterial strategies. Drug repositioning is a relatively recent strategy employed in drug development; testing approved drugs on new targets considerably reduces the time and cost of this process. The combined computational and in vitro approach further reduces the number of compounds to be tested in vivo. Our aim was to identify a subset of known drugs able to prevent HP1043 binding to DNA promoters. This result was reached through evaluation by molecular docking the binding capacity of about 14,350 molecules on the HP1043 dimer in both conformations, bound and unbound to the DNA. Employing an ad hoc pipeline including MMGBSA molecular dynamics, a selection of seven drugs was obtained. These were tested in vitro by electrophoretic mobility shift assay to evaluate the HP1043–DNA interaction. Among these, three returned promising results showing an appreciable reduction of the DNA-binding activity of HP1043. Overall, we applied a computational methodology coupled with experimental validation of the results to screen a large number of known drugs on one of the H. pylori essential transcription factors. This methodology allowed a rapid reduction of the number of drugs to be tested, and the drug repositioning approach considerably reduced the drug design costs. Identified drugs do not belong to the same pharmaceutical category and, by computational analysis, bound different cavities, but all display a reduction of HP1043 binding activity on the DNA. |
format | Online Article Text |
id | pubmed-9135449 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-91354492022-05-27 Targeting the Essential Transcription Factor HP1043 of Helicobacter pylori: A Drug Repositioning Study Antoniciello, Federico Roncarati, Davide Zannoni, Annamaria Chiti, Elena Scarlato, Vincenzo Chiappori, Federica Front Mol Biosci Molecular Biosciences Antibiotic-resistant bacterial pathogens are a very challenging problem nowadays. Helicobacter pylori is one of the most widespread and successful human pathogens since it colonizes half of the world population causing chronic and atrophic gastritis, peptic ulcer, mucosa-associated lymphoid tissue-lymphoma, and even gastric adenocarcinoma. Moreover, it displays resistance to numerous antibiotics. One of the H. pylori pivotal transcription factors, HP1043, plays a fundamental role in regulating essential cellular processes. Like other bacterial transcription factors, HP1043 does not display a eukaryote homolog. These characteristics make HP1043 a promising candidate to develop novel antibacterial strategies. Drug repositioning is a relatively recent strategy employed in drug development; testing approved drugs on new targets considerably reduces the time and cost of this process. The combined computational and in vitro approach further reduces the number of compounds to be tested in vivo. Our aim was to identify a subset of known drugs able to prevent HP1043 binding to DNA promoters. This result was reached through evaluation by molecular docking the binding capacity of about 14,350 molecules on the HP1043 dimer in both conformations, bound and unbound to the DNA. Employing an ad hoc pipeline including MMGBSA molecular dynamics, a selection of seven drugs was obtained. These were tested in vitro by electrophoretic mobility shift assay to evaluate the HP1043–DNA interaction. Among these, three returned promising results showing an appreciable reduction of the DNA-binding activity of HP1043. Overall, we applied a computational methodology coupled with experimental validation of the results to screen a large number of known drugs on one of the H. pylori essential transcription factors. This methodology allowed a rapid reduction of the number of drugs to be tested, and the drug repositioning approach considerably reduced the drug design costs. Identified drugs do not belong to the same pharmaceutical category and, by computational analysis, bound different cavities, but all display a reduction of HP1043 binding activity on the DNA. Frontiers Media S.A. 2022-05-11 /pmc/articles/PMC9135449/ /pubmed/35647033 http://dx.doi.org/10.3389/fmolb.2022.887564 Text en Copyright © 2022 Antoniciello, Roncarati, Zannoni, Chiti, Scarlato and Chiappori. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Molecular Biosciences Antoniciello, Federico Roncarati, Davide Zannoni, Annamaria Chiti, Elena Scarlato, Vincenzo Chiappori, Federica Targeting the Essential Transcription Factor HP1043 of Helicobacter pylori: A Drug Repositioning Study |
title | Targeting the Essential Transcription Factor HP1043 of Helicobacter pylori: A Drug Repositioning Study |
title_full | Targeting the Essential Transcription Factor HP1043 of Helicobacter pylori: A Drug Repositioning Study |
title_fullStr | Targeting the Essential Transcription Factor HP1043 of Helicobacter pylori: A Drug Repositioning Study |
title_full_unstemmed | Targeting the Essential Transcription Factor HP1043 of Helicobacter pylori: A Drug Repositioning Study |
title_short | Targeting the Essential Transcription Factor HP1043 of Helicobacter pylori: A Drug Repositioning Study |
title_sort | targeting the essential transcription factor hp1043 of helicobacter pylori: a drug repositioning study |
topic | Molecular Biosciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9135449/ https://www.ncbi.nlm.nih.gov/pubmed/35647033 http://dx.doi.org/10.3389/fmolb.2022.887564 |
work_keys_str_mv | AT antoniciellofederico targetingtheessentialtranscriptionfactorhp1043ofhelicobacterpyloriadrugrepositioningstudy AT roncaratidavide targetingtheessentialtranscriptionfactorhp1043ofhelicobacterpyloriadrugrepositioningstudy AT zannoniannamaria targetingtheessentialtranscriptionfactorhp1043ofhelicobacterpyloriadrugrepositioningstudy AT chitielena targetingtheessentialtranscriptionfactorhp1043ofhelicobacterpyloriadrugrepositioningstudy AT scarlatovincenzo targetingtheessentialtranscriptionfactorhp1043ofhelicobacterpyloriadrugrepositioningstudy AT chiapporifederica targetingtheessentialtranscriptionfactorhp1043ofhelicobacterpyloriadrugrepositioningstudy |