Synergistic efficacy of polymyxin B and indole-3-carbinol against Klebsiella pneumoniae bloodstream infection

Abstract

Klebsiella pneumoniae (K. pneumoniae), a major hospital-acquired infection, poses a significant threat to life and global public health. Indole compounds have been found to affect bacterial growth through multiple metabolic pathways, but the mechanism is unclear. To investigate the combination of indole-3-carbinol (I3C) and polymyxin B (PMNB) as a new strategy to combat bloodstream infections caused by K. pneumoniae. The antibacterial synergy between I3C and PMNB was comprehensively assessed both in vitro and in vivo through a variety of methods including drug sensitivity tests, checkerboard assays, time-kill curves, growth curves, and a murine bloodstream infection model. Furthermore, the mechanisms underpinning the synergistic antibacterial effects of I3C as an adjuvant to PMNB were explored and substantiated via cell morphology studies, reactive oxygen species (ROS) analysis, efflux pump activity assays, and transcriptomic analyses. When combined with PMNB, I3C exhibited synergistic antibacterial effects in vitro, affecting cell morphology and ROS production. Moreover, this combination significantly enhanced outcomes in a murine model of K. pneumoniae infection, evidenced by increased survival rates, recovery of body weight, reduced bacterial loads, and diminished pathological damage. Additionally, I3C influenced the lipid metabolism pathways of K. pneumoniae and altered the structure of the cellular membrane. This investigation evaluates the synergistic antibacterial properties of I3C and PMNB as adjuvants and offers a detailed analysis of their capacity to augment the bactericidal efficacy of PMNB by modulating bacterial lipid metabolism. This work provides a solid research foundation for managing K. pneumoniae infections in clinical practice.

Keywords: Antimicrobial activity; Indole-3-carbinol; Klebsiella pneumoniae; Lipid metabolism; Polymyxin B.