Neutrons for antibiotics: probing cell membranes with neutron beams

Bacteria may soon replace viruses as primary pandemic concern. In our shrinking antibiotic arsenal, polymyxin B stands out as a last-resort drug capable of breaching the bacterial outer membrane – though not without side effects. A study now published brought together expertise from different neutron facilities toexamine this process at the molecular scale using neutron scattering on model bacterial membranes. This work was also featured as a cover image for the journal issue.

Bacteria fall into two main categories: Gram-positive and Gram-negative. A key distinction is the additional impermeable membrane protecting Gram-negative bacteria. This unique biological barrier shields them from antibiotics, making Gram-negative bacteria a special concern. The outer membrane differs from typical cell membranes, consisting of double layers of lipid molecules (phospholipid bilayers): it is made of phospholipids on its inner layer and large molecules called lipopolysaccharides (LPS) on its outer surface. The LPS molecules form an impermeable palisade against many antibiotics. Polymyxin B can breach the outer membrane by destabilizing LPS interactions, leading to irreparable damage and cell death. But how does this work?

Cell membranes are approximately five nanometres thick, which make detailed atomic-scale investigation extremely challenging. Neutron reflectometry offers a solution to measure the structure of these ultra-thin layers.Quantum mechanics tells us that neutrons behave both as particles and as waves. They are thus able to create interference patterns when reflecting off thin films. “It’s an effect similar to the colours seen in soap bubbles, but at the nanometre scale,” explains Nicoló Paracini, first author of the publication and former PhD student in ISIS and instrument scientist at the ILL, “The so-called cold neutrons, with wavelengths comparable to X-rays (in the angstrom range), are perfectly suited to the study of biological membranes. Cold neutrons carry only a few meV of kinetic energy rather than the several keV of X-rays, preventing membrane damage during measurement.”