The role of outer membrane and efflux pumps in the resistance of gram-negative bacteria. Can we improve drug access?

Many antibiotics inhibit gram-negative bacteria less effectively than gram-positive bacteria, because the outer membrane permeability barrier allows only a slow influx of drugs, and the small number of drug molecules that traversed the outer membrane are efficiently inactivated or pumped out back into the medium, the last-mentioned process often catalyzed by widely distributed multidrug efflux pumps. Paradoxically, drugs of advanced design that are not inactivated enzymatically, such as beta-lactamase-stable lactams and fluoroquinolones, tend to select for more resistant mutants which overexpress these pumps. The drug-hypersensitive phenotype of efflux-deficient mutants suggests that inhibition of the pumps may be a good way not only to combat resistance of this type, but also to make 'intrinsically' resistant gram-negative bacteria susceptible to a wide range of drugs. Alternatively, the outer membrane can be permeabilized by cationic peptides, thereby sensitizing bacteria especially to lipophilic antibiotics.