Grant: CIHR Fellowship

Proteins carry out nearly all cellular functions. Some proteins are anchored in cell membranes and control the exchange of molecules into and out of cells. Antibiotic resistant bacteria have developed ways to efficiently drive antibiotics out of the cell interior using membrane protein pumps. Understanding and combatting antibiotic resistance is a frontier problem in scientific research as worldwide demand for antibiotics has increased and progress developing new antibiotics has slowed. The proposed research programme develops new mass spectrometry tools to directly measure the molecular interactions between membrane protein pumps, lipid molecules in the surrounding membrane, and antibiotics. MacAB-TolC is a membrane protein pump in E. coli that confers resistance to macrolide antibiotics. The pump is an intricate molecular machine, assembled from six copies of MacA, two copies of MacB, and three copies of TolC, that bridges the inner and outer cell membranes. The proposed studies aim to determine the effects of the surrounding membrane lipids on antibiotic recognition and are anticipated to reveal trends in how antibiotics are recognized and pumped out of cells. Furthermore, the research programme aims to determine the molecular details involved in the step-by-step mechanisms for pump assembly, to devise new strategies to completely abrogate pump formation.