Core Proteomic Analysis of Unique Metabolic Pathways of Salmonella enterica for the Identification of Potential Drug Targets (original) (raw)
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Genomics driven approach for identification of novel therapeutic targets in Salmonella enterica
Gene, 2018
Salmonella enterica is a causative agent of enteric and systemic salmonellosis that affects human and many other animal species. Due to the emergence of drug-resistant strains, available drugs against S. enterica infection are no more effective as before. Thus, there is an urgent need to develop new therapeutic strategies. The current study aims at prioritizing therapeutic targets by an in-silico genomics driven method. The method involves searching proteins of each Salmonella strain for essentiality, virulence and antibiotic-resistance and host-pathogen protein-protein interactions. Using subtractive genomics approach, we further confirmed that none of the selected protein shares sequence homology with any human (host) protein and also with proteins from human symbiotic gut flora. Pathway analysis of these screened proteins revealed associated biological processes. Presence of proteins in pathogen-specific pathways was used as one of the assessment property in the subsequent scorin...
PLOS ONE
Salmonella entericaserovar Typhimurium (S. Typhimurium) is a highly adaptive pathogenic bacteria with a serious public health concern due to its increasing resistance to antibiotics. Therefore, identification of novel drug targets forS. Typhimurium is crucial. Here, we first created a pathogen-host integrated genome-scale metabolic network by combining the metabolic models of human andS. Typhimurium, which we further tailored to the pathogenic state by the integration of dual transcriptome data. The integrated metabolic model enabled simultaneous investigation of metabolic alterations in human cells andS. Typhimurium during infection. Then, we used the tailored pathogen-host integrated genome-scale metabolic network to predict essential genes in the pathogen, which are candidate novel drug targets to inhibit infection. Drug target prioritization procedure was applied to these targets, and pabB was chosen as a putative drug target. It has an essential role in 4-aminobenzoic acid (PAB...
BioMed Research International
The emergence of novel pathogenic strains with increased antibacterial resistance patterns poses a significant threat to the management of infectious diseases. In this study, we aimed at utilizing the subtractive genomic approach to identify novel drug targets against Salmonella enterica subsp. enterica serovar Poona strain ATCC BAA-1673. We employed in silico bioinformatics tools to subtract the strain-specific paralogous and host-specific homologous sequences from the bacterial proteome. The sorted proteome was further refined to identify the essential genes in the pathogenic bacterium using the database of essential genes (DEG). We carried out metabolic pathway and subcellular location analysis of the essential proteins of the pathogen to elucidate the involvement of these proteins in important cellular processes. We found 52 unique essential proteins in the target proteome that could be utilized as novel targets to design newer drugs. Further, we investigated these proteins in t...
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Salmonella enterica sv. Typhimurium is an established model organism for Gram-negative, intracellular pathogens. Owing to the rapid spread of resistance to antibiotics among this group of pathogens, new approaches to identify suitable target proteins are required. Based on the genome sequence of S. Typhimurium and associated databases, a genome-scale metabolic model was constructed. Output was based on an experimental determination of the biomass of Salmonella when growing in glucose minimal medium. Linear programming was used to simulate variations in the energy demand while growing in glucose minimal medium. By grouping reactions with similar flux responses, a subnetwork of 34 reactions responding to this variation was identified (the catabolic core). This network was used to identify sets of one and two reactions that when removed from the genome-scale model interfered with energy and biomass generation. Eleven such sets were found to be essential for the production of biomass pr...
Interactome Analysis for Identification of Common Drug Targets in Salmonella Species
Journal of Health and Medical Informatics, 2019
A wide variety of human population is infected with different species of Salmonella causing salmonellosis. At present, the major hurdle in treating infection is the development of resistance to existing antibiotics. Therefore, there is a need to identify new drug targets so that new drugs can be designed that can cure the infection efficiently. Here, we have design an interactome for all species of Salmonella using its essential and non-homologous protein to humans. So that, all types of infections of Salmonella can be treated with single antibiotic. 1399 essential proteins of Salmonella have been analyzed using interactome studies. We found 09 proteins as putative drug targets that can be used to treat all species of Salmonella.
Biotechnology Letters, 2022
Purpose The efficacy of drugs against Salmonella infection have compromised due to emerging XDR H58 strain. There is a dire need to find novel antimicrobial drug targets as well as drug candidates to cure by the XDR strain of Salmonella. It is observed that the complete genome sequence of the XDR H58 strain contains a large number of hypothetical proteins with unknown cellular and biological functions. Hence, it is indispensable to annotate these proteins functionally as well as structurally to identify novel drug targets. Methods In the current study, a comparative genomics and proteomics based approach was applied to find the novel drug targets in XDR strain while comparing the MDR and NR strains of Salmonella typhi. Results The characterization of * 350 hypothetical proteins were performed through determination of their physio-chemical properties, sub-cellular localization, functional annotation, and structure-based studies. As a result, only five proteins were prioritized as essential, druggable, and virulent proteins. Moreover, only one protein i.e. WP_000916613.1 was functionally annotated with high confidence and subjected to further structure-based analysis. Conclusion The current study presents a hypothetical protein from the XDR S. typhi proteome as a potential pharmacological target against which novel therapeutic candidates may be predicted. The outcome of the current study may lead to formulate a general set of pipelines for better understanding of the role of hypothetical proteins in pathogenesis of not only Salmonella but also for other pathogens.
SALMONELLABASE - An online database of druggable targets of Salmonella species
Bioinformation, 2012
Salmonellosis is one of the most common and widely distributed food borne diseases caused by Salmonella serovars. The emergence of multi drug resistant strains has become a threatening public health problem and targeting unique effectors of this pathogen can be considered as a powerful strategy for drug design. SalmonellaBase is an online web portal serving as an integrated source of information about Salmonella serovars with the data required for the structural and functional studies and the analysis of druggable targets in Salmonella. We have identified several target proteins, which helps in the pathogenicity of the organism and predicted their structures. The database will have the information on completely sequenced genomes of Salmonella species with the complete set of protein sequences of the respective strains, determined structures, predicted protein structures and biochemical pathways of the respective strains. In addition, we have provided information about name and source of the protein, Uniprot and Protein Data Bank codes and literature information. Furthermore, SalmonellaBase is linked to related databases and other resources. We have set up a web interface with different search and display options so that users have the ability to get the data in several ways. SalmonellaBase is a freely available database.
Genome subtraction for novel target definition in Salmonella typhi
Bioinformation, 2009
Large genomic sequencing projects of pathogens as well as human genome leads to immense genomic and proteomic data which would be very beneficial for the novel target identification in pathogens. Subtractive genomic approach is one of the most useful strategies helpful in identification of potential targets. The approach works by subtracting the genes or proteins homologous to both host and the pathogen and identify those set of gene or proteins which are essential for the pathogen and are exclusively present in the pathogen. Subtractive genomic approach is employed to identify novel target in salmonella typhi. The pathogen has 4718 proteins out of which 300 are found to be essential ("indispensable to support cellular life") in the pathogen with no human homolog. Metabolic pathway analyses of these 300 essential proteins revealed that 149 proteins are exclusively involved in several metabolic pathway of S. typhi. 8 metabolic pathways are found to be present exclusively in the pathogen comprising of 27 enzymes unique to the pathogen. Thus, these 27 proteins may serve as prospective drug targets. Sub-cellular localization prediction of the 300 essential proteins was done which reveals that 11 proteins lie on the outer membrane of the pathogen which could be probable vaccine candidates.
Gene Reports, 2020
Background: Essential genes are defined as the minimal gene set required to support bacterial life. In order to develop new antimicrobials to treat multidrug-resistant pathogens, such as serovars of Salmonella enterica, the identification of essential genes is crucial. Methodology: In the present work, we hypothesize that essential genes within a group of evolutionary closely related organisms may be highly conserved. We, therefore, conducted an extensive comparative genomic analysis of 44 genome sequences representing 17 serovars of S. enterica to gain an improved understanding of conserved essential genes for its survival. Results: Pan-genome estimates indicate that the genus Salmonella displays an open pan-genome structure comprising a reservoir of 10,775 gene families. Of these, 2847, 4657, and 3271 constitute the core gene families (CGFs), dispensable gene families (DGFs), and strain-specific gene families (SSGFs), respectively. The pangenome family tree based on the presence/absence of gene families is highly concordant with the 16S rRNA tree, though the former provides a more robust phylogenetic resolution. The Clusters of Orthologous Groups of proteins (COGs) database categorized the vast majority of the CGFs (40.9%) to metabolism, whereas a large proportion of the DGFs (70.6%) was uncharacterized. Homology analysis of the CGFs against the Database of essential genes (DEG) identified 1695 essential CGFs (E-CGFs). Of these, 687 are experimentally verified as essential in Salmonella, 1157 are identified in ≥2 species, 159 are conserved in ≥7 species, and 538 were present in at least one species. Thus, for the species, S. enterica 69%, 52%, and 31% of the genome are dedicated to the core, essential, and dispensable functions, respectively. Conclusion: The E-CGFs identified may serve as important targets for the development of novel antimicrobials, and their detailed analysis may shed new light on a better understanding of Salmonella's survival.
The Journal of biological chemistry, 2009
Salmonella are closely related to commensal Escherichia coli but have gained virulence factors enabling them to behave as enteric pathogens. Less well studied are the similarities and differences that exist between the metabolic properties of these organisms that may contribute toward niche adaptation of Salmonella pathogens. To address this, we have constructed a genome scale Salmonella metabolic model (iMA945). The model comprises 945 open reading frames or genes, 1964 reactions, and 1036 metabolites. There was significant overlap with genes present in E. coli MG1655 model iAF1260. In silico growth predictions were simulated using the model on different carbon, nitrogen, phosphorous, and sulfur sources. These were compared with substrate utilization data gathered from high throughput phenotyping microarrays revealing good agreement. Of the compounds tested, the majority were utilizable by both Salmonella and E. coli. Nevertheless a number of differences were identified both between Salmonella and E. coli and also within the Salmonella strains included. These differences provide valuable insight into differences between a commensal and a closely related pathogen and within different pathogenic strains opening new avenues for future explorations.