ABSTRACT
Antimicrobial peptides and proteins are produced by virtually all organisms (13) as a part of their innate immune defense system (4). Several hundred antimicrobial peptides have been characterized from organisms ranging from bacteria and fungi to plants and animals. Examples include defensins from human plasma, magainins from frog skin, cecropins from insect larvae, and thionins from plants. The evolutionary success of such antimicrobials implies strategies for selectivity and for overcoming drug resistance. As a class they do not have a deleterious effect on the organisms that produce them. This fact alone rules out nonspecific mechanisms of action, such as leakage of the cytoplasmic content. Not all cationic peptides show antibacterial activity, and the membrane-permeabilizing effect of amphiphilic cationic peptides (1,5) does not account for the selectivity of polymyxins against gram-negative organisms. In fact, the membrane disruption by polymyxins is observed at a mole fraction that is more than 100 times the minimum inhibitory concentrations (6-8). Results reviewed in this chapter show that the antibacterial effect of polymyxin B (PxB) is due to a novel mechanism with far-reaching implications.
