Streptococcus pneumoniae is widely recognized as the main cause of bacterial pneumonia among all age groups. Other important gram-positive, gram-negative and atypical bacteria causing pneumonia majorly infect children and infants. Despite abundant occurrence of bacterial pneumonia, there is no specific antibiotic therapy available. On the other hand non-specific therapies are less effective and may influence bacterial resistance. Therefore, search for novel drug targets for pathogen is highly necessary. The current study suggested novel potential drug targets through the subtractive and comparative genomics approach. Putative drug targets were identified from highly virulent strain of Streptococcus pneumoniae using target identification (TiD) software and compared with other 12 pneumonia causing pathogens. The putative targets were prioritized through druggability analysis, virulence analysis, metabolic pathway enrichment followed by functional annotations and interactome network. Prioritization of 74 drug targets revealed that 42 of them were enzymes which included 29 new targets and seven chokepoint enzymes. Twenty (out of 74) potential targets are proposed as hub genes through interactome analysis and explored their significance in survival of the pathogen. Comparative analysis of 20 hub genes represents that 15 are enzymes and five are non-enzymes. Functional annotation of two chokepoint hub enzymes namely, peptidoglycan bridge formation alanyltransferase MurN (fibB) and PTS mannitol transporter subunit IIA (mltF) were significantly enriched in peptidoglycan biosynthesis and phosphotransferase system (PTS) respectively. Therefore these enzymes would be of prior interest for rational design of targeted therapy against bacterial pneumonia.