Investigating the molecular transmission dynamics of blaNDM in antibiotic-selective environments

Abstract

Carbapenem resistance mediated by bla_NDM-encoded metallo-beta-lactamases is often linked to ISAba125, an insertion sequence from the IS30 family, which is widely distributed among critical and high-priority bacterial pathogens. The rapid dissemination of ISAba125-linked bla_NDM in both nosocomial and community-acquired infections presents a serious challenge to healthcare systems and pharmaceutical industries. Despite the urgency of this issue, the factors driving bla_NDM spread and the molecular mechanisms governing ISAba125 mobility remain poorly understood. In this study, we engineered the genomes of Vibrio cholerae and Escherichia coli to investigate the mobility of bla_NDM under controlled conditions both with and without the genetically linked ISAba125. We also examined the transmission efficiency and the stability of bla_NDM in environments with and without sublethal antibiotic concentrations. Our in vitro findings were validated in a rabbit ileal loop model. The results revealed that antibiotic pressure significantly influences the mobility of bla_NDM, shedding light on the molecular dynamics of its transmission. These insights are crucial for developing strategies to curb the spread of bla_NDM and mitigate the growing threat of carbapenem resistance in bacterial pathogens.IMPORTANCEInsertion sequences are the simplest form of mobile genetic elements that play a critical role in the adaptation of bacteria, allowing them to rapidly acquire new traits like resistance genes that enhance their survival. ISAba125 is one such insertion sequence that facilitates the spread of bla_NDM, contributing to the global challenge of carbapenem resistance. In this study, we developed reporter strains that could be used as a valuable tool for investigating the dynamics of ISAba125-linked bla_NDMsh-ble and evaluated the transposition frequency of ISAba125-linked bla_NDMsh-ble in the presence and absence of sublethal concentration of antibiotics. Our results demonstrated that ISAba125 enhances the spread of bla_NDMsh-ble under sublethal concentration of antibiotics that induces SOS response.

Keywords: antibiotic resistance; horizontal gene transfer; insertion sequences; metallo-beta-lactamases; mobile genetic elements.