Emergence of silent NDM-1 carbapenemase gene in carbapenem-susceptible Klebsiella pneumoniae: Clinical implications and epidemiological insights

Abstract

The global dissemination of carbapenemase genes, particularly bla_NDM-1, poses a significant threat to public health. While research has mainly focused on strains with phenotypic resistance, the impact of silent resistance genes has been largely overlooked. This study documents the first instance of silent bla_NDM-1 in a cluster of clonally related carbapenem-susceptible K. pneumoniae strains from a single patient. Despite initial effectiveness of carbapenem therapy, the patient experienced four recurrent lung infections over five months, indicating persistent K. pneumoniae infection. Genomic sequencing revealed all strains harbored bla_NDM-1 on the epidemic IncX3 plasmid. A deletion within the upstream promoter region (P_ISAba125) of bla_NDM-1 hindered its expression, resulting in phenotypic susceptibility to carbapenems. However, in vitro bactericidal assays and a mouse infection model showed that K. pneumoniae strains with silent bla_NDM-1 exhibited significant tolerance to carbapenem-mediated killing. These findings demonstrate that silent bla_NDM-1 can mediate both phenotypic susceptibility and antibiotic tolerance. In silico analysis of 1986 bla_NDM sequences showed that 1956 (98.5%) retained the original promoter P_ISAba125. Given that previous genomic sequencing typically targets carbapenem-resistant strains, accurately assessing the prevalence of silent bla_NDM remains challenging. This study highlights the hidden threat of silent resistance genes to clinical antimicrobial therapy and calls for enhanced clinical awareness and laboratory detection.