In Silico Identification of Novel Drug Targets in Acinetobacter Baumannii by Subtractive Genomic Approach

Abstract

Objective: Multiple drug resistance (MDR) in bacteria, particularly Gram-negative bacilli, has significantly hindered the treatment of infections caused by these bacteria. This results in the need for identifying new drugs and drug targets for these bacteria. The objective of this study was to identify novel drug targets in Acinetobacter baumannii which has emerged as a medically important pathogen due to an increasing number of infections caused by it and its MDR property.Methods: In our study, we implemented in silico subtractive genomics approach to identify novel drug targets in A. baumannii American type culture collection 17978. Various databases and online software were used to build a systematic workflow involving comparative genomics, metabolic pathways analysis, and drug target prioritization to identify pathogen-specific novel drug targets.Results: First, 458 essential proteins were retrieved from a database of essential genes, and by performing BLASTp against Homo sapiens, 246 human non-homologous essential proteins were selected of 458 proteins. Metabolic pathway analysis performed by Kyoto Encyclopedia of Genes and Genomes–Kyoto Automatic Annotation Server revealed that these 246 essential non-homologous proteins were involved in 66 metabolic pathways. Among these metabolic pathways, 12 pathways were found to be unique to Acinetobacter that involved 37 non-homologous essential proteins. Of these essential non-homologous proteins, 19 proteins were found in common as well as unique metabolic pathways and only 18 proteins were unique to Acinetobacter. Finally, these target proteins were filtered to 9 potential targets, based on subcellular localization and assessment of druggability using Drug bank, ChEMBL, and literature.Conclusion: Our study identified nine potential drug targets which are novel targets in A. baumannii and can be used for designing drugs against these proteins. These drugs will be pathogen specific with no side effects on human host, as the potential drug targets are human non-homologous.

Proteome based mapping and molecular docking revealed DnaA as a potential drug target against Shigella sonnei

“…These 7 pathways include a two-component system, bacterial secretion system, Quorum sensing, Monobactam biosynthesis, metabolism of microbe within diverse environments, and synthesis of the secondary metabolites. The findings of pathways identification which are specific to the pathogen are in line with the results of L. interrogans , A. baumannii, and S. saprophyticus reported by ( Amineni et al, 2010 , Goyal et al, 2018 , Shahid et al, 2020 ). A total of 16 essential proteins of S. sonnei were associated with these 7 pathways.…”

“…The subcellular location of the DnaA was identified using Psortb. The subcellular location of protein helps in determining the protein function as well as its potential as a potent target ( Goyal & Citu, 2018 ). DnaA was found to be cytoplasmic protein as predicted by Psortb.…”

“…The prediction of subcellular localization provides a fast and relatively cost-effective way to obtain information about a protein particular function. Besides, it has been found that proteins can locate at multiple sites, so localization is a critical aspect of designing any therapeutic agent ( Goyal & Citu, 2018 ). Subcellular localization of the target proteins of Shigella sonnei (Strain Ss046) was identified through Psortb ( Yu et al, 2010 ).…”

In Silico Subtractive Proteomics Approach for Identification of Potential Drug Targets in Staphylococcus saprophyticus

“…Subcellular localization prediction provides a fast and relatively cost-effective method of obtaining information regarding the function of a particular protein. Moreover, it was found that proteins can localize at multiple sites, therefore localization is a critical aspect of designing any therapeutic agent [28]. Cytoplasmic proteins are considered more suitable as drug targets because proteins located on the membrane are difficult to purify and analyze [26].…”

In Silico Core Proteomics and Molecular Docking Approaches for the Identification of Novel Inhibitors against Streptococcus pyogenes

“…As a result, targeting such genes may prove fatal and disrupt human metabolism. Selection of non-homologous proteins not found in Homo sapiens can reduce the risk of adverse events and cross-reactivity [54]. We screened 145 non-homologous proteins to avoid such unfavorable situations and toxicity.…”