Identification of Potential Drug Targets in Helicobacter pylori Using In Silico Subtractive Proteomics Approaches and Their Possible Inhibition through Drug Repurposing

Abstract

The class 1 carcinogen, Helicobacter pylori, is one of the World Health Organization’s high priority pathogens for antimicrobial development. We used three subtractive proteomics approaches using protein pools retrieved from: chokepoint reactions in the BIOCYC database, the Kyoto Encyclopedia of Genes and Genomes, and the database of essential genes (DEG), to find putative drug targets and their inhibition by drug repurposing. The subtractive channels included non-homology to human proteome, essentiality analysis, sub-cellular localization prediction, conservation, lack of similarity to gut flora, druggability, and broad-spectrum activity. The minimum inhibitory concentration (MIC) of three selected ligands was determined to confirm anti-helicobacter activity. Seventeen protein targets were retrieved. They are involved in motility, cell wall biosynthesis, processing of environmental and genetic information, and synthesis and metabolism of secondary metabolites, amino acids, vitamins, and cofactors. The DEG protein pool approach was superior, as it retrieved all drug targets identified by the other two approaches. Binding ligands (n = 42) were mostly small non-antibiotic compounds. Citric, dipicolinic, and pyrophosphoric acid inhibited H. pylori at an MIC of 1.5–2.5 mg/mL. In conclusion, we identified potential drug targets in H. pylori, and repurposed their binding ligands as possible anti-helicobacter agents, saving time and effort required for the development of new antimicrobial compounds.

Computer-Based Identification of Potential Druggable Targets in Multidrug-Resistant Acinetobacter baumannii: A Combined In Silico, In Vitro and In Vivo Study

“…To the best of our knowledge, this is the first time that OGEE was used to retrieve essential proteins. Most previous similar studies have used databases such as the Database of Essential Genes (DEG) and Geptop instead [ 12 , 13 , 15 , 17 ]. Avoiding possible undesired effects in human hosts is important, so essential proteins that are non-homologous to the human proteome were identified.…”

“…The antibacterial activity of these organic acids has been previously reported in several studies [ 67 , 68 , 69 ]. It has been reported that citric acid exhibits antibacterial activity against Helicobacter pylori and Pseudomonas aeruginosa [ 12 , 68 , 70 ]. Over et al reported the antibacterial activity of some organic acids, including both citric acid and tartaric acid on Escherichia coli O157:H7, Listeria monocytogenes and Salmonella typhimurium [ 71 ].…”

“…Using the subtractive proteomics approach, potential drug targets were previously identified in several other pathogens, including Escherichia coli , Helicobacter pylori , Mycobacterium avium , Pseudomonas aeruginosa , Shigella flexneri , Staphylococcus aureus , Staphylococcus saprophyticus , Stenotrophomonas maltophilia and Streptococcus pneumoniae [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. Although potential drug targets in A. baumannii have been identified in former studies [ 20 , 21 , 22 ], the current study proceeds to further validate the data obtained by the in silico approach.…”

Aspartate α-decarboxylase a new therapeutic target in the fight against Helicobacter pylori infection

“…The availability of the genomic sequences of pathogenic bacteria has provided huge data that can be used for identifying potential drug and vaccine targets through subtractive genomic, proteomic or transcriptomic approaches (Nandode et al, 2012;Yan and Gao, 2020). Using a subtractive proteomic approach, we previously identified 17 essential targets in H. pylori with 42 possible Drugbank ligands, of which several small organic acids were potential ligands for many of the retrieved essential targets (Ibrahim et al, 2020). These molecules have a well-known antibacterial activity, such as (S)-3-phenyllactic acid (Mu et al, 2012), citric acid (Adamczak et al, 2020), malonic acid (Feng et al, 2010), dipicolinic acid (Jadamus et al, 2005), and D-tartaric acid (Hu et al, 2019;Coban, 2020).…”

“…ADC was identified as a Mycobacterium tuberculosis drug target inhibited by pyrazinamide (Gopal et al, 2020). Malonic acid was proposed as a potential inhibitor of the H. pylori ADC enzyme (Ibrahim et al, 2020).…”