Resistance to antibiotics and chemotherapeutic agents is a growing medical concern. Multidrug resistance (MDR), in which cells are resistant to a number of unrelated drugs, is a particular problem in cancer chemotherapy.
One mechanism that underlies MDR results from a normally beneficial cellular process. Multidrug transporters, proteins embedded in the membrane of every cell from the most humble bacterium to the most sophisticated human cell, provide an important, nonspecific form of protection by purging toxic compounds from the cell.
"Multidrug transporters are a part of a defense mechanism universal to all organisms that allows them to remove cytotoxic molecules out of the cytoplasm," said Hassane Mchaourab, Ph.D., associate professor of Molecular Physiology and Biophysics, at Vanderbilt University Medical Center, the senior author on the study.
But, in doing so, they contribute to cells becoming resistant to some therapeutic drugs, most notably antibiotics and chemotherapy drugs.
In the May 13 issue of Science, Vanderbilt University Medical Center scientists reveal details about the structure and function of a multidrug transporter called MsbA that may help advance the design of new antibiotics and chemotherapy drugs that will be able to evade these transporters.
The first step in designing drugs that can defy these proteins is determining the structure and function of these transporters.
The basic structure of MsbA had previously been determined through crystal structure analysis, which provides a visual representation of an individual protein. However, a static model, which a crystal structure provides, reveals little about the way that protein functions.