Unveiling Druggable Segments in Klebsiella pneumoniae KPHS_11890: An Integrated DRKG- MD Study

Klebsiella pneumoniae (K. pneumoniae) , a multidrug-resistant Gram-negative bacillus, represents a significant global health threat due to its role in hospital-acquired infections and the emergence of carbapenem-resistant hypervirulent strains. This study integrates the Drug Repurposing Knowledge Graph (DRKG) with molecular dynamics (MD) simulations to identify and validate stable structural segments of the KPHS_11890 gene, which encodes a membrane fusion protein of the AcrAB-TolC efflux pump that is critical for antibiotic resistance in K. pneumoniae . Using the PyKEEN framework, a knowledge graph embedding model was trained on a comprehensive dataset combining DrugBank, K. pneumoniae strain FASTA sequences, and NCBI databases, achieving a Hits@10 score of 0.1602 and an adjusted arithmetic mean rank of 0.0238. The model predicted KPHS_11890 as a top candidate, validated by 100-ns molecular dynamics simulations using Amber 24, which revealed stable segments in the α-helical domain, the extended strand domain, and the random coil domain. These segments, identified through low root mean square fluctuation (RMSF) values and conserved secondary structures, are critical for AcrA interactions with AcrB and TolC, offering potential drug-binding sites for efflux pump inhibitors. This integrated DRKG-MD approach efficiently pinpoints high-potential targets and elucidates their structural basis, thereby accelerating the development of novel anti-resistance therapeutics.