Dataset Information

Genome-Based Drug Target Identification in Human Pathogen Streptococcus gallolyticus.

ABSTRACT: Streptococcus gallolysticus (Sg) is an opportunistic Gram-positive, non-motile bacterium, which causes infective endocarditis, an inflammation of the inner lining of the heart. As Sg has acquired resistance with the available antibiotics, therefore, there is a dire need to find new therapeutic targets and potent drugs to prevent and treat this disease. In the current study, an in silico approach is utilized to link genomic data of Sg species with its proteome to identify putative therapeutic targets. A total of 1,138 core proteins have been identified using pan genomic approach. Further, using subtractive proteomic analysis, a set of 18 proteins, essential for bacteria and non-homologous to host (human), is identified. Out of these 18 proteins, 12 cytoplasmic proteins were selected as potential drug targets. These selected proteins were subjected to molecular docking against drug-like compounds retrieved from ZINC database. Furthermore, the top docked compounds with lower binding energy were identified. In this work, we have identified novel drug and vaccine targets against Sg, of which some have already been reported and validated in other species. Owing to the experimental validation, we believe our methodology and result are significant contribution for drug/vaccine target identification against Sg-caused infective endocarditis.

SUBMITTER: Qureshi NA

PROVIDER: S-EPMC8027347 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Genome-Based Drug Target Identification in Human Pathogen Streptococcus gallolyticus.

Qureshi Nosheen Afzal NA Bakhtiar Syeda Marriam SM Faheem Muhammad M Shah Mohibullah M Bari Ahmed A Mahmood Hafiz M HM Sohaib Muhammad M Mothana Ramzi A RA Ullah Riaz R Jamal Syed Babar SB

Frontiers in genetics 20210325

Streptococcus gallolysticus (Sg) is an opportunistic Gram-positive, non-motile bacterium, which causes infective endocarditis, an inflammation of the inner lining of the heart. As Sg has acquired resistance with the available antibiotics, therefore, there is a dire need to find new therapeutic targets and potent drugs to prevent and treat this disease. In the current study, an in silico approach is utilized to link genomic data of Sg species with its proteome t ...[more]

PMID: 33841489

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Project description:Streptococcus gallolyticus subsp. gallolyticus, a member of the group D streptococci, is normally found in the bovine rumen and human gut. It is an opportunistic pathogen that was recently determined to be a bacterial driver of colorectal cancer, in addition to causing other diseases, such as infective endocarditis, bacteremia, neonatal meningitis, and septicemia. As an emerging pathogen, not much is known about this bacterium, its virulence mechanisms, or its virulence regulatory pathways. Previous studies suggest that S. gallolyticus subsp. gallolyticus uses a ComRS pathway, one of many Streptococcus quorum-sensing circuitries, for competence. However, thus far, the ubiquitous ComABCDE pathway has not been studied, nor has its regulatory role in S. gallolyticus subsp. gallolyticus We therefore sought to study the S. gallolyticus subsp. gallolyticus ComABCDE quorum-sensing pathway and have identified its peptide pheromone, which is termed the competence-stimulating peptide (CSP). We further determined that this peptide regulates the production of bacteriocin-like inhibitory substances (BLISs), a phenotype that has been linked with the ComABCDE pathway in both Streptococcus pneumoniae and Streptococcus mutans Our data show that S. gallolyticus subsp. gallolyticus TX20005 produces a 21-mer CSP signal, which differs from CSP signals of other Streptococcus species in that its active form begins three residues after the double-glycine leader signal of the ComC precursor peptide. Additionally, our data suggest that this peptide might not be related to competence induction, as opposed to CSP signaling peptides in other Streptococcus species. This study provides the first evidence that S. gallolyticus subsp. gallolyticus utilizes quorum sensing to eliminate competitors, presenting a potential pathway to target this emerging human pathogen.IMPORTANCEStreptococcus gallolyticus subsp. gallolyticus is an emerging human pathogen known as a causative agent of infective endocarditis, and recently, of colorectal cancer. In this work, we revealed a functional quorum-sensing circuitry in S. gallolyticus subsp. gallolyticus, including the identification of the central signaling peptide pheromone, competence-stimulating peptide (CSP), and the regulatory role of this circuitry in the production of bacteriocin-like inhibitory substances (BLISs). This work uncovered a mechanism by which this bacterium outcompetes other bacterial species and thus provides a potential tool to study this opportunistic pathogen.

Project description:BackgroundStreptococcus gallolyticus subsp. gallolyticus is an important causative agent of infective endocarditis (IE) but the knowledge on virulence factors is limited and the pathogenesis of the infection is poorly understood. In the present study, we established an experimental in vitro IE cell culture model using EA.hy926 and HUVEC cells to investigate the adhesion and invasion characteristics of 23 Streptococcus gallolyticus subsp. gallolyticus strains from different origins (human IE-derived isolates, other human clinical isolates, animal isolates). Adhesion to eight components of the extracellular matrix (ECM) and the ability to form biofilms in vitro was examined in order to reveal features of S. gallolyticus subsp. gallolyticus endothelial infection. In addition, the strains were analyzed for the presence of the three virulence factors gtf, pilB, and fimB by PCR.ResultsThe adherence to and invasion characteristics of the examined S. gallolyticus subsp. gallolyticus strains to the endothelial cell line EA.hy926 differ significantly among themselves. In contrast, the usage of three different in vitro models (EA.hy926 cells, primary endothelial cells (HUVECs), mechanical stretched cells) revealed no differences regarding the adherence to and invasion characteristics of different strains. Adherence to the ECM proteins collagen I, II and IV revealed the highest values, followed by fibrinogen, tenascin and laminin. Moreover, a strong correlation was observed in binding to these proteins by the analyzed strains. All strains show the capability to adhere to polystyrole surfaces and form biofilms. We further confirmed the presence of the genes of two known virulence factors (fimB: all strains, gtf: 19 of 23 strains) and demonstrated the presence of the gene of one new putative virulence factor (pilB: 9 of 23 strains) by PCR.ConclusionOur study provides the first description of S. gallolyticus subsp. gallolyticus adhesion and invasion of human endothelial cells, revealing important initial information of strain variability, behaviour and characteristics of this as yet barely analyzed pathogen.

Dataset Information

Genome-Based Drug Target Identification in Human Pathogen Streptococcus gallolyticus.

Publications

Genome-Based Drug Target Identification in Human Pathogen <i>Streptococcus gallolyticus</i>.

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