Understanding blaNDM-1 gene regulation in CRKP infections: toward novel antimicrobial strategies for hospital-acquired pneumonia

• Published in: Molecular medicine (Cambridge, Mass.) Vol. 30; no. 1; p. 29
• Main Authors: Ding, Liang, Yang, Zheng, Sun, Baier
• Format: Journal Article
• Language: English
• Published: England BMC 23.02.2024
• Subjects: Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antimicrobial strategy; blaNDM-1 gene; Carbapenems - pharmacology; Carbapenems - therapeutic use; CRKP; Drug resistance; Drug Resistance, Bacterial - genetics; Gene expression regulation; Hospital-acquired pneumonia; Hospitals; Humans; Imipenem; Klebsiella Infections - drug therapy; Klebsiella Infections - genetics; Klebsiella Infections - microbiology; Klebsiella pneumoniae - genetics; Pneumonia; Hospital-acquired pneumonia; Antimicrobial strategy; blaNDM-1 gene; Gene expression regulation; CRKP; Drug resistance
• ISSN: 1528-3658; 1528-3658
• DOI: 10.1186/s10020-024-00794-y

The escalating challenge of Carbapenem-resistant Klebsiella pneumoniae (CRKP) in hospital-acquired pneumonia (HAP) is closely linked to the blaNDM-1 gene. This study explores the regulatory mechanisms of blaNDM-1 expression and aims to enhance antibacterial tactics to counteract the spread and infection of resistant bacteria. KP and CRKP strains were isolated from HAP patients' blood samples. Transcriptomic sequencing (RNA-seq) identified significant upregulation of blaNDM-1 gene expression in CRKP strains. Bioinformatics analysis revealed blaNDM-1 gene involvement in beta-lactam resistance pathways. CRISPR-Cas9 was used to delete the blaNDM-1 gene, restoring sensitivity. In vitro and in vivo experiments demonstrated enhanced efficacy with Imipenem and Thanatin or Subatan combination therapy. KP and CRKP strains were isolated with significant upregulation of blaNDM-1 in CRKP strains identified by RNA-seq. The Beta-lactam resistance pathway was implicated in bioinformatics analysis. Knockout of blaNDM-1 reinstated sensitivity in CRKP strains. Further, co-treatment with Imipenem, Thanatin, or Subactam markedly improved antimicrobial effectiveness. Silencing blaNDM-1 in CRKP strains from HAP patients weakens their Carbapenem resistance and optimizes antibacterial strategies. These results provide new theoretical insights and practical methods for treating resistant bacterial infections.