Biologic membranes are composed basically of lipid, protein, and lipoprotein. The cytoplasmic membrane acts as a diffusion barrier for water, ions, nutrients, and transport systems. Most workers now believe that membranes are a lipid matrix with globular proteins randomly distributed to penetrate through the lipid bilayer. A number of antimicrobial agents can cause disorganization of the membrane. These agents can be divided into cationic, anionic, and neutral agents. The best-known compounds are polymyxin B and colistemethate (polymyxin E). These high-molecular-weight octapeptides inhibit Gram-negative bacteria that have negatively charged lipids at the surface. Since the activity of the polymyxins is antagonized by Mg2+ and Ca2+, they probably competitively displace Mg2+ or Ca2+ from the negatively charged phosphate groups on membrane lipids. Basically, polymyxins disorganize membrane permeability so that nucleic acids and cations leak out and the cell dies. The polymyxins are of virtually no use as systemic agents since they bind to various ligands in body tissues and are potent toxins for the kidney and nervous system. Gramicidins are also membrane-active antibiotics that appear to act by producing aqueous pores in the membranes. They also are used only topically.