Multidrug-resistant bacteria: overcoming antibiotic permeability barriers of Gram-negative bacteria

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.