Targeting the Essential Transcription Factor HP1043 of Helicobacter pylori: A Drug Repositioning Study

Abstract

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.

Insights into the Orchestration of Gene Transcription Regulators in Helicobacter pylori

“…Accordingly, increasing efforts have been put forward in searching for new compounds able to inhibit the growth of pathogens by acting specifically on new molecular targets for novel drug discovery. As a result, many transcriptional regulators have been considered and studied as valid drug targets with promising results, including the H. pylori HP1043 regulatory protein [185,186]. Furthermore, the two-component systems (TCS) have received increasing attention [187].…”

Current trends and future prospects of drug repositioning in gastrointestinal oncology

“…Furthermore, in vivo and in vitro anti-tumor and growth suppression effects of ivermectin were demonstrated on GC, showing that ivermectin suppressed MKN1 cells growth through yes-associated protein 1 (YAP1) downregulation ( Nambara et al, 2017 ). To identify drugs capable of inhibiting the DNA-binding activity of the helicobacter pylori transcription factor HP104, a combination of computational and in vitro methods led to the discovery of three promising drugs, including temoporfin, trientine, and tetraethylenepentamine, for potential antibacterial applications ( Antoniciello et al, 2022 ). Table 4 provides a summary of available repurposed drugs in GC.…”

Two-component regulatory systems in Helicobacter pylori and Campylobacter jejuni: Attractive targets for novel antibacterial drugs

“…To date, some investigations have been carried out in order to validate HsrA and ArsR as effective therapeutic targets against H. pylori infection as well as discovering low-molecular weight inhibitors of these RRs exhibiting strong bactericidal activities against antibiotic-resistant strains of this pathogen ( González et al., 2019a ; González et al., 2019b ; González et al., 2020 ; Antoniciello et al., 2022 ; González et al., 2022 ). Notably, some of the novel antibacterial candidates evaluated in these studies, including natural flavonoids and 1,4-dihydropiridines, have shown in vitro antimicrobial activities in the range of those observed with first-line conventional antibiotics ( González et al., 2021 ; González et al., 2022 ).…”