Strategies for bypassing the membrane barrier in multidrug resistant Gram-negative bacteria

In Gram-negative bacteria, the envelope is a sophisticated barrier protecting the cell against external toxic compounds. Membrane transporters, e.g., porins or efflux pumps, are main filters regulating the internal accumulation of various hydrophilic molecules.Regarding bacterial susceptibility towards antibacterial agents, membrane permeability is part of the early bacterial defense. The bacterium manages the translocation process, influx and efflux, to control the intracellular concentration of various molecules. Antibiotics and biocides are substrates of these mechanisms and the continuing emergence of multidrug resistant isolates is a growing worldwide health concern. Different strategies could be proposed to bypass the bacterial membrane barrier, comprising influx and efflux mechanisms, in order to restore the activity of antibiotics against resistant bacteria.

► Global bacterial regulators control the expression of transport mechanisms including influx (porins) and efflux (pumps)
► They conjointly contribute to the membrane barrier, the first line of bacterial defense against antibacterial agents.
► Increasing the antibiotic influx and blocking the efflux improve the intracellular concentration of antibiotics.
► Various strategies bypassing the membrane barrier can restore the activity of antibiotics against resistant bacteria.