A structural view of drug-induced cooperativity on the multi-drug resistance ABC transporter BmrA -2-.

Drug resistance is a major public health threat, as it results in an untreatable pathology with very poor prognosis. Often, drug resistance is associated with multi-drug resistance, which is the ability of a microbe or cancer cell to resist to many structurally unrelated drugs. The disease is thus resistant to virtually all the therapeutic arsenal. One of the major mechanisms to create this resistance is the active efflux out of the cell of the active compounds. This simply decreases the drug concentration inside the cell bellow cytotoxic levels. We investigate this mechanism in this proposal. We are investigating the structural transition of the transporter to expel the drug, having already collected 4 datasets along the transition path. This proposal is the continuation of a previous proposal, to obtain the last dataset before publication. Data have already been collected on the IBS Glacios, but limited at 6Å resolution. We are applying for Krios beamtime to reach higher resolution.