Li, C.; Budge, L. P.; Driscoll, C. D.; Willardson, B. M.; Allman, G. W.; Savage, P. B. J. Am. Chem. Soc. 1999, 121, 931-940. Incremental conversion of outer-membrane permeabilizers into potent antibiotics for Gram-negative bacteria.

ompounds in a series of cholic acid derivatives, designed to mimic the activities of polymyxin B and its derivatives, act as both potent antibiotics and effective permeabilizers of the outer membranes of gram-negative bacteria. Some of these compounds rival polymyxin B in antibacterial activity against gram-negative bacteria and are also very active against gram-positive organisms. Other compounds interact synergistically with hydrophobic antibiotics to inhibit bacterial growth.

We have developed a series of cholic acid derivatives that includes compounds that act as potent antibiotics against gram-negative and gram-positive bacteria. In addition, compounds within this series effectively permeabilize the outer membranes of gram-negative bacteria, thereby sensitizing the bacteria to hydrophobic antibiotics. These cholic acid derivatives were developed () to mimic the bactericidal behavior of polymyxin B (PMB) and the outer membrane-permeabilizing properties of truncated versions of PMB, such as deacyl PMB () and PMB nonapeptide (). The cholic acid derivatives contain elements conserved among the polymyxin family of antibiotics, that is, a cluster of three amine groups and a hydrophobic chain. Cholic acid derivatives containing these two elements are potent antibiotics, while those lacking the hydrophobic chain effectively sensitize gram-negative bacteria to erythromycin, novobiocin, and rifampin.