Because of the permeability barrier provided by the outer membrane (OM), gram-negative bacteria are inherently resistant to many hydrophobic
antibiotics. This resistance limits the arsenal of
antibiotics that are effective in treating
gram-negative bacterial infections. Compounding this problem, strains of gram-negative bacteria have emerged that display specific resistance mechanisms for effective
antibiotics. As a means of expanding the arsenal of effective
antibiotics for gram-negative bacteria, compounds that permeabilize the OM to hydrophobic substances have been developed. These compounds are typically cationic, amphiphilic molecules that can be prepared from
peptides or
steroids. Effective OM permeabilizers sensitize gram-negative bacteria to hydrophobic
antibiotics, including
erythromycin,
fusidic acid,
novobiocin and
rifampin. These
antibiotics are generally not useful in treating
gram-negative bacterial infections because they traverse the OM ineffectively. The use of OM permeabilizers, in combination with hydrophobic
antibiotics, may provide additional means of controlling growth of gram-negative bacteria. This review describes classes of permeabilizers, including those derived from
peptides, and recently reported examples based on
steroids.