Colistin kills bacteria by targeting lipopolysaccharide in the cytoplasmic membrane - primary data for all experiments described in the manuscript

Colistin is an antibiotic of last resort, but has poor efficacy and
resistance is a growing problem. Whilst it is well established that
colistin disrupts the bacterial outer membrane by selectively targeting
lipopolysaccharide (LPS), it was unclear how this led to bacterial
killing. We discovered that MCR-1 mediated colistin resistance in
Escherichia coli is due to modified LPS at the cytoplasmic rather than
outer membrane. In doing so, we also demonstrated that colistin exerts
bactericidal activity by targeting LPS in the cytoplasmic membrane. We
then exploited this information to devise a new therapeutic approach.
Using the LPS transport inhibitor murepavadin, we were able to cause LPS
accumulation in the cytoplasmic membrane of Pseudomonas aeruginosa, which
resulted in increased susceptibility to colistin in
vitro and improved treatment efficacy in vivo. These
findings reveal new insight into the mechanism by which colistin kills
bacteria, providing the foundations for novel approaches to enhance
therapeutic outcomes.