Characterization and targeting of deleterious mutations in Carbapenemase-producing Klebsiella pneumoniae: insights from variant calling, Computer-aided drug design, and DFT analysis
摘要
The emergence of Carbapenemase-producing Klebsiella pneumoniae (CP-KP) strains is becoming a significant global concern. Rising resistance rates in these strains significantly impact available treatment options. Therefore, this present research aims to identify the existence of antibiotic-resistance genes in clinical isolates of CP-KP strains. Whole-genome sequencing data from 17 CP-KP isolates were analyzed to identify genetic variants associated with antibiotic resistance. Among the 85 variants, a deleterious mutation, E466D, was identified in DNA gyrase B (GyrB), associated with fluoroquinolone (FQ) resistance. Therefore, flavonoids were used to target mutated GyrB. Flavonoids have been extensively investigated for their antibacterial properties, as they tend to inhibit the growth of many pathogenic microorganisms, including multidrug-resistant bacteria. A total of 222 flavonoids were subjected to virtual screening against the GyrB. The docking affinity of all the ligands with GyrB was within the range of − 3.7 to − 7.9 kcal mol− 1. Further, the top 10 compounds having stronger docking energy compared to the reference compound (− 6.1 kcal mol− 1) were subjected to MD simulation in triplicate for 250 ns to examine the ligand’s stability against GyrB. Out of the 10 compounds, five compounds, namely, theaflavine, neobavaisoflavone, trifolirhizin, isosilybinin, and glycitin, showed good stability. Identification of natural compounds with high binding affinity for mutated GyrB indicates that they may be used as innovative therapeutic treatments. This finding might serve as a foundation for upcoming investigations and clinical studies aimed at creating potent remedies treating infections caused by K. pneumoniae that are resistant to FQ.