Clavanin permeabilizes target membranes via two distinctly different pH-dependent mechanisms

The pH dependence of the antimicrobial and membrane activity of clavanin A, a peptide antibiotic that is rich in histidines and glycines, was analyzed in growth and membrane leakage experiments. Clavanin A more effectively inhibited the growth of the test organism Lactobacillus sake when the pH of the medium was lowered. Whereas the wild-type peptide efficiently released fluorophores from unilamellar vesicles at neutral pH according to a nonspecific permeabilization mechanism, it did not permeabilize model bilayers at low pH. It was therefore suggested that this peptide uses a distinct mode of action under acidic conditions different than that used around neutral pH. However, at low pH, the membrane is still the target for clavanin A, as the peptide collapsed both vital transmembrane proton gradients and ion gradients under these conditions. Clavanin A did not act as a ionophore across phospholipid bilayers, indicating that membrane constituents other than membrane phospholipids are involved in the dissip...