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.

Keywords: Streptococcus gallollyticus; drug prioritization; infective endocarditis; pan-genome; subtractive proteomics.

FIGURE 1

Complete workflow of drug target identification in Sg using in silico approaches.

FIGURE 2

Blue native cocrystallized ligand and red dock ligand.

FIGURE 3

Interaction of 16S rRNA methyltransferase B with ZINC01532584 (colored in red). The interacting residues (green) are shown bonding (dotted lines) with the ligand.

FIGURE 4

Interaction of chromosomal replication initiator protein DnaA with ZINC71782058 (colored in red). The interacting residues (green) are shown bonding (dotted lines) with the ligand.

FIGURE 5

Interaction of transcriptional regulator CtsR with ZINC79090716 (colored in red). The interacting residues (green) are shown bonding (dotted lines) with the ligand.

FIGURE 6

Interaction of phosphotransferase system (PTS) fructose transporter subunit IIA with ZINC01638334 (colored in red). The interacting residues (green) are shown bonding (dotted lines) with the ligand.

FIGURE 7

Interaction of penicillin-binding protein 2A with ZINC16942644 (colored in red). The interacting residues (green) are shown bonding (dotted lines) with the ligand.

FIGURE 8

Interaction of UDP-N-acetylmuramoyl-tripeptide–D-alanyl-D-alanine ligase with ZINC14681317 (colored in red). The interacting residues (green) are shown bonding (dotted lines) with the ligand.

FIGURE 9

Interaction of AraC family transcriptional regulator with ZINC71781167 (colored in red). The interacting residues (green) are shown making bonding (dotted lines) with the ligand.

FIGURE 10

Interaction of DNA polymerase III subunit alpha with ZINC38653615 (colored in red). The interacting residues (green) are shown bonding (dotted lines) with the ligand.

FIGURE 11

Interaction of 50S ribosomal protein L28 with ZINC03872713 (colored in red). The interacting residues (green) are shown bonding (dotted lines) with the ligand.

FIGURE 12

Interaction of 2-isopropylmalate synthase with ZINC40448986 (colored in red). The interacting residues (green) are shown bonding (dotted lines) with the ligand.

FIGURE 13

Interaction of ribosome-binding factor A with ZINC01235906 (colored in red). The interacting residues (green) are shown making bonding (dotted lines) with the ligand.

FIGURE 14

Interaction of DNA-binding response regulator with ZINC38140720 (colored in red). The interacting residues (green) are shown bonding (dotted lines) with the ligand.