Multidrug Resistance

In this chapter we cover non-specific, intrinsic multidrug-resistance (MDR), which provides bacteria with protection from a wide spectrum of xenobiotic compounds, including medically relevant antibiotics. There are two main components to this resistance –the general permeability barrier of the cell envelope, and the active efflux of toxic compounds outside the cell. Active efflux is clinically one of the most important mechanisms underlying antibiotic resistance. This resistance is provided by energized transporters, which have low substrate specificity and as such provide the first internal line of defence to xenobiotic stress. The ability of bacterial pathogens to up-regulate the production of these protein pump complexes (commonly referred to as multidrug efflux-pumps or multidrug resistance (MDR)-pumps) allows time for the adaptive resistance mechanisms to develop. Although MDR-pumps are widely spread in all groups of bacteria, in Gram-negative organisms the second membrane provides an additional layer of protection by limiting the permeation of drugs into the cell. We take a closer look at the different transporter groups involved in MDR and the organization and energy requirements of these pumping systems. We focus on the tripartite efflux-pumps, which form highly modular trans-envelope assemblies in Gram-negative bacteria and play a central role in the drug resistance of these organisms.