Murepavadin is a broad-spectrum outer membrane permeabiliser
Murepavadin is a Pseudomonas-specific antibiotic that targets LPS transport protein LptD. However, whilst the mode of action of murepavadin is well defined, the mechanism by which the drug gains access to LptD remains unresolved. Here, we demonstrate a self-directed uptake mechanism for murepavadin, whereby binding to lipid A induces outer membrane disruption, enabling entry of the antibiotic into the periplasm and access to LptD. Murepavadin-LPS interactions were not specific to P. aeruginosa, however, and were found to cause OM disruption across a wide range of Gram-negative bacteria, resulting in increased antibiotic susceptibility. We also discovered that murepavadin-mediated OM disruption sensitised E. coli to the membrane attack complex of the complement system. In conclusion, murepavadin is a broad-spectrum membrane permeabiliser, which results in increased bacterial susceptibility to antibiotics and host defences.