Subtractive genomics and drug repurposing strategies for targeting Streptococcus pneumoniae: insights from molecular docking and dynamics simulations.

Abstract

Introduction: Streptococcus pneumoniae is a Gram-positive bacterium responsible for severe infections such as meningitis and pneumonia. The increasing prevalence of antibiotic resistance necessitates the identification of new therapeutic targets. This study aimed to discover potential drug targets against S. pneumoniae using an in silico subtractive genomics approach.

Methods: The S. pneumoniae genome was compared to the human genome to identify non-homologous sequences using CD-HIT and BLASTp. Essential genes were identified using the Database of Essential Genes (DEG), with consideration for human gut microflora. Protein-protein interaction analyses were conducted to identify key hub genes, and gene ontology (GO) studies were performed to explore associated pathways. Due to the lack of crystal structure data, a potential target was modeled in silico and subjected to structure-based virtual screening.

Results: Approximately 2,000 of the 2,027 proteins from the S. pneumoniae genome were identified as non-homologous to humans. The DEG identified 48 essential genes, which was reduced to 21 after considering human gut microflora. Key hub genes included gpi, fba, rpoD, and trpS, associated with 20 pathways. Virtual screening of 2,509 FDA-approved compounds identified Bromfenac as a leading candidate, exhibiting a binding energy of -26.335 ± 29.105 kJ/mol.

Discussion: Bromfenac, particularly when conjugated with AuAgCu₂O nanoparticles, has demonstrated antibacterial and anti-inflammatory properties against Staphylococcus aureus. This suggests that Bromfenac could be repurposed as a potential therapeutic agent against S. pneumoniae, pending further experimental validation. The approach highlights the potential for drug repurposing by targeting proteins essential in pathogens but absent in the host.