Multidrug resistance and efflux pumps: insights from molecular dynamics simulations.

Evolution of bacteria resistant to the most diverse antibiotics is posing one of the major threats to public health. Particular alarm is raised by those genetic lines that develop phenotypes simultaneously resistant to multiple drugs. Among the different mechanisms leading to multidrug resistance, multidrug efflux pumps raise particular concern. These are large macromolecular constructs localised at cell boundaries, which are able to actively bind and transport out of the cell several chemically uncorrelated substrates. In this last decade, computer modelling has proved to be a valuable tool for the investigation of multiple drug-efflux systems at the molecular level. In particular, molecular dynamics simulations unveiled several aspects of the molecular mechanisms governing the recognition and transport of drugs by these systems. Computer-aided protocols constitute a bottom-up reductionist approach that has the privilege of obtaining clean data referring intrinsically to those single parts of the efflux process explicitly taken into account. Combining computational data to the experimental determinations may therefore help in the definition of possible general criteria limiting the action of these systems against both patented and new putative antibiotic agents. Here, we review the most relevant contributions by computational scientists to the understanding of multidrug-efflux systems in the recent past. Particular care is put in the description of the dynamical features of multidrug exporters, a valuable piece of information for which computer modelling represents one of the best investigation tools available at present.