Multidrug Efflux in the Context of Two-Membrane Cell Envelopes

The trans-envelope drug efflux in Gram-negative bacteria demands assembly of specialized protein complexes that in addition to inner membrane transporters include periplasmic membrane fusion proteins and outer membrane channels due to the presence of a double membrane. These complexes are highly versatile and constitute a major antimicrobial resistance mechanism of Gram-negative bacteria. The modular organization of the tripartite assemblies in Gram-negative bacteria allows them to accommodate a wide array of multidrug efflux transporters enabling efflux across both the inner and the outer membranes of the cell envelope. This chapter focuses on the structures and mechanisms of trans-envelope multidrug efflux pumps from Gram-negative bacteria. We summarize the current state of the field and the emerging model for multidrug efflux in the context of two membranes.