Abstract
Most clinical antibiotics do not have efficacy against Gram-negative pathogens, mainly because these cells are protected by the permeability barrier comprising the two membranes with active efflux. The emergence of multidrug-resistant Gram-negative strains threatens the utility even of last resort therapeutic treatments. Significant efforts at different levels of resolution are currently focused on finding a solution to this nonpermeation problem and developing new approaches to the optimization of drug activities against multidrug-resistant pathogens. The exceptional efficiency of the Gram-negative permeability barrier is the result of a complex interplay between the two opposing fluxes of drugs across the two membranes. In this review, we describe the current state of understanding of the problem and the recent advances in theoretical and empirical approaches to characterization of drug permeation and active efflux in Gram-negative bacteria.