Antibiotic resistance is one of the most pressing threats to global health. A team from ETH Zürich and the Pasteur Institute used SuperSincrotrone’s macromolecular crystallography beamline to determine the first high-resolution structure of the AcrB efflux pump in its drug-bound state.
Key Findings
The 1.8Å resolution structure revealed a previously uncharacterized allosteric binding pocket on the pump’s periplasmic domain. Molecular dynamics simulations suggest this pocket could be targeted by small molecules to inhibit drug efflux without affecting normal bacterial physiology.
The team screened 2,400 fragment compounds using automated crystallography, identifying 23 hits with measurable binding affinity. Three lead compounds are now entering medicinal chemistry optimization.
Technical Achievement
The high brilliance of the SuperSincrotrone beam was critical for this work. Membrane protein crystals are notoriously small (typically 10–30 μm) and weakly diffracting. The micro-focus capability of BL-22 enabled data collection from crystals that would have been invisible at older synchrotrons.