Lipid A on bacterial extracellular vesicles mediates resistance to Polymyxins

The continuous emergence of multidrug-resistant bacterial pathogens poses a major global healthcare challenge, with Klebsiella pneumoniae (Kp) being a prominent threat. We conducted a comprehensive study on Kp's antibiotic resistance mechanisms, focusing on outer membrane vesicles (OMVs) and polymyxin, a last-resort antibiotic.

Our research demonstrated that OMVs protect bacteria from polymyxins. OMVs derived from polymyxin B (PB)-stressed Kp exhibited heightened protective efficacy due to increased vesiculation, compared to OMVs from unstressed Kp. OMVs also shielded other Enterobacteriaceae family members, Pseudomonas aeruginosa, and Legionella pneumophila. This was validated ex vivo and in vivo using precision cut lung slices (PCLS) and Galleria mellonella. In both models, OMVs protected Kp from PB and reduced the associated stress response on protein level. We observed significant changes in the lipid composition of OMVs upon PB treatment, affecting their binding capacity to PB. This lipid A-dependent protective effect against PB was confirmed in vitro using artificial vesicles. Moreover, artificial vesicles successfully protected Kp from PB both ex vivo and in vivo.

The findings indicate that OMVs act as protective shields for bacteria by binding to polymyxins, effectively serving as decoys and preventing antibiotic interaction with the bacterial cell surface. Our findings provide valuable insights into the mechanisms underlying antibiotic cross-protection and offer potential avenues for the development of novel therapeutic interventions to address the escalating threat of multidrug-resistant bacterial infections.

Publication History

Article published online:
01 March 2024