Anti-bacterial compounds from Indian curry-leaf tree Murraya koenigii have potential to inhibit carbapenem-resistant Streptococcus pneumoniae

Problems considered Spike in the mortality rates due to pneumococcal infections post-COVID-19 has raised clinical concerns globally. β-lactam antibiotic-susceptibility in the causative organism, Streptococcus pneumoniae has been compromised due to non-synonymous single nucleotide polymorphisms (nsSNPs) in different penicillin-binding protein (PBP) targets. Carbapenem-resistant S. pneumoniae strains have further constricted the pharmacologically safe therapeutic options. Methods In-house sequenced whole genomes of meropenem and cefotaxime resistant Indian and global isolates were used to retrieve parent and mutant proteins. Anti-bacterial phtytochemicals (ABPs) from Indian curry-leaf tree Murraya koenigii were identified using database-mining. ABPs were screeened based on pharmacokinetics, and toxicity profiles. Site-specific molecular docking studies revealed ABPs‘ affinity towards the targets as compared to control drug meropenem. Coarse-grained and normal-mode molecular dynamics simulation further asserted the interactive stability of the chosen compounds. Results From the whole genomes (n = 28) of meropenem and cefotaxime resistant (MIC ≥0.5 μg/ml) Indian and global isolates, ∼50 nsSNPs in the active-site regions of PBP1A, PBP2B and PBP2X were identified. Based on pharmacological safety and high drug-likeliness, 10 ABPs were funnelled down from 226 ABPs in M. koenigii. A pyrano-carbazole alkaloid koenine was further prioritized as the most efficient candidate based on consistently high binding affinity (binding energies −7.7 to −8.9 kcal/mol), low inhibition constant (0.69–3.5 μM) and low structural fluctuations (<1.1 Å), against mutant targets as compared to meropenem. Conclusion The study encourages experimental validation of koenine against pneumococci and also promotes the use of similar phytochemical resources for evaluation against emerging drug-resistant pathogens harbouring mutant targets.