Revealing Cell-Surface Intramolecular Interactions in the BlaR1 Protein of Methicillin-Resistant Staphylococcus aureus by NMR Spectroscopy

In methicillin-resistant Staphylococcus aureus, β-lactam antibiotic resistance is mediated by the transmembrane protein BlaR1. The antibiotic sensor domain BlaRS and the L2 loop of BlaR1 are on the membrane surface. We used NMR to investigate interactions between BlaRS and a water-soluble peptide from L2. This peptide binds BlaRS proximal to the antibiotic acylation site as an amphipathic helix. Acylation of BlaRS by penicillin G does not disrupt binding. These results suggest a signal transduction mechanism whereby the L2 helix, partially embedded in the membrane, propagates conformational changes caused by BlaRS acylation through the membrane via transmembrane segments, leading to antibiotic resistance.