TY - JOUR TI - Colistin kills bacteria by targeting lipopolysaccharide in the cytoplasmic membrane AU - Sabnis, Akshay AU - Hagart, Katheryn LH AU - Klöckner, Anna AU - Becce, Michele AU - Evans, Lindsay E AU - Furniss, R Christopher D AU - Mavridou, Despoina AI AU - Murphy, Ronan AU - Stevens, Molly M AU - Davies, Jane C AU - Larrouy-Maumus, Gérald J AU - Clarke, Thomas B AU - Edwards, Andrew M A2 - Cole, Philip A A2 - Gao, Lianghui A2 - van Schaik, Willem VL - 10 PY - 2021 DA - 2021/04/06 SP - e65836 C1 - eLife 2021;10:e65836 DO - 10.7554/eLife.65836 UR - https://doi.org/10.7554/eLife.65836 AB - 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 (OM) 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 OM. In doing so, we also demonstrated that colistin exerts bactericidal activity by targeting LPS in the cytoplasmic membrane (CM). 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 CM 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. KW - Polymyxin KW - Colistin KW - lipopolysaccharide KW - phospholipids KW - Pseudomonas KW - E. coli JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -