​Gram-negative bacteria, which are responsible for two-thirds of bacterial infections acquired in hospital, are surrounded by a protective outer membrane (OM). This OM severely limits the variety of antibiotic molecules effective against Gram-negative pathogens and, as antibiotic resistance increases, so does the need to solve the problem of permeating the OM.

Polymyxin B (PmB) is a last-resort antibiotic used to treat many hospital-acquired bacterial infections. Scientists from Newcastle University and STFC used neutron reflectometry on the INTER and CRISP reflectometers to reveal how PmB penetrates the outer membrane of Gram-negative bacteria. The OM has a dense outer layer of lipopolysaccharide (LPS), a glycolipid directly targeted by PmB.

The researchers studied the PmB–OM interaction in vitro, and their results (published in PNAS) showed that in vivo results are only reproduced when the LPS is in a liquid crystalline phase, which occurs at body temperature. These findings not only explain why PmB only works at, or above, body temperature but also support the fundamental notion that bacteria actively control the viscosity of their outer membranes as temperatures vary.

Polymyxin B (PmB) represents a currently rare type of antibiotic, which acts directly on the OM. Improving our understanding of its mode of action offers a distinct starting point for new antibiotic development.

Related publication: “Liquid crystalline bacterial outer membranes are critical for antibiotic susceptibility" PNAS, vol. 115, no. 32, E7587–E7594, DOI: 10.1073/pnas.1803975115

Authors: Nicolò Paracini (Newcastle University), Luke A. Clifton (ISIS), Maximilian W. A. Skoda (ISIS), and Jeremy H. Lakey (Newcastle University).

Instrument: INTER and CRISP