Specificity and tunability of bacterial efflux pumps: a new role for the proton motive force?*

Efflux pumps on the cell membrane offer an important mechanism by which bacteria become resistant to a wide range of antibiotics, posing serious problems for public health. I will discuss ongoing work towards a quantitative characterization of the kinetics of proton-powered efflux pumps, particularly concerning their role in multidrug resistance. Motivated by experimentally determined information about the properties of various cellular pumps, we construct a series of models treating their operation as a Markov jump process between states associated with different protein conformations and bound ligands. We derive an expression for the efflux rate, demonstrating its specific dependence on the parameters characterizing conditions in the cell. We find that the efflux is driven not only by a combined "proton motive force", but rather, it depends distinctly on the proton concentration gradient and the electric potential. Furthermore, changes to the pH in the intermembrane space shift the range of drug binding affinities at which the pump is most effective. As such, bacterial populations may be able to adaptively tune this pH to respond to particular drugs used in treatment. This offers new insight into the possible origins of broad antibiotic resistance in hopes of helping to guide the development of treatments that can overcome it.