Additive and synergistic membrane permeabilization by antimicrobial (lipo)peptides and detergents.
Certain antibiotic peptides are thought to permeabilize membranes of pathogens by effects that are also observed for simple detergents, such as membrane thinning and disordering, asymmetric bilayer expansion, toroidal pore formation, and micellization. Here we test the hypothesis that such peptides act additively with detergents when applied in parallel. Additivity is defined analogously to a fractional inhibitory concentration index of unity, and the extent and mechanism of leakage is measured by the fluorescence lifetime-based vesicle leakage assay using calcein-loaded vesicles. Good additivity was found for the concerted action of magainin 2, the fungicidal lipopeptide class of surfactins from Bacillus subtilis QST713, and the detergent octyl glucoside, respectively, with the detergent C12EO8. Synergistic or superadditive action was observed for fengycins from B. subtilis, as well as the detergent CHAPS, when combined with C12EO8. The results illustrate two mechanisms of synergistic action: First, maximal leakage requires an optimum degree of heterogeneity in the system that may be achieved by mixing a graded with an all-or-none permeabilizer. (The optimal perturbation should be focused to certain defect structures, yet not to the extent that some vesicles are not affected at all.) Second, a cosurfactant may enhance the bioavailability of a poorly soluble peptide. The results are important for understanding the concerted action of membrane-permeabilizing compounds in biology as well as for optimizing formulations of such antimicrobials for medical applications or crop protection.
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada; Department of Biophysics and Chemistry, University of Michigan, Ann Arbor, Michigan.
Hiren
H
Patel
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada.
Quang
Q
Huynh
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada.
Dominik
D
Bärlehner
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada; Institut für Medizinische Physik und Biophysik, Universität Leipzig, Leipzig, Germany. Electronic address: heiko.heerklotz@utoronto.ca.
Heiko
H
Heerklotz
D000595:Amino Acid Sequence; D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000737:chemistry; D002463:Cell Membrane Permeability; D003902:Detergents / Q000378:metabolism* / Q000494:pharmacology*; D004357:Drug Synergism; D005960:Glucosides / Q000378:metabolism / Q000494:pharmacology; D055666:Lipopeptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D054806:Magainins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008823:Micelles; D013816:Thermodynamics
D023181:Antimicrobial Cationic Peptides; D003902:Detergents; D005960:Glucosides; D055666:Lipopeptides; D054806:Magainins; D008823:Micelles; C049972:fengycin; C018619:octyl-beta-D-glucoside