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Guanidino groups greatly enhance the action of antimicrobial peptidomimetics against bacterial cytoplasmic membranes.

ABSTRACT: Antimicrobial peptides or their synthetic mimics are a promising class of potential new antibiotics. Herein we assess the effect of the type of cationic side chain (i.e., guanidino vs. amino groups) on the membrane perturbing mechanism of antimicrobial ?-peptide-?-peptoid chimeras. Langmuir monolayers composed of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylglycerol (DPPG) were used to model cytoplasmic membranes of both Gram-positive and Gram-negative bacteria, while lipopolysaccharide Kdo2-lipid A monolayers were mimicking the outer membrane of Gram-negative species. We report the results of the measurements using an array of techniques, including high-resolution synchrotron surface X-ray scattering, epifluorescence microscopy, and in vitro antimicrobial activity to study the molecular mechanisms of peptidomimetic interaction with bacterial membranes. We found guanidino group-containing chimeras to exhibit greater disruptive activity on DPPG monolayers than the amino group-containing analogues. However, this effect was not observed for lipopolysaccharide monolayers where the difference was negligible. Furthermore, the addition of the nitrobenzoxadiazole fluorophore did not reduce the insertion activity of these antimicrobials into both model membrane systems examined, which may be useful for future cellular localization studies.

SUBMITTER: Andreev K

PROVIDER: S-EPMC4125507 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Guanidino groups greatly enhance the action of antimicrobial peptidomimetics against bacterial cytoplasmic membranes.

Andreev Konstantin K Bianchi Christopher C Laursen Jonas S JS Citterio Linda L Hein-Kristensen Line L Gram Lone L Kuzmenko Ivan I Olsen Christian A CA Gidalevitz David D

Biochimica et biophysica acta 20140528 10

Antimicrobial peptides or their synthetic mimics are a promising class of potential new antibiotics. Herein we assess the effect of the type of cationic side chain (i.e., guanidino vs. amino groups) on the membrane perturbing mechanism of antimicrobial α-peptide-β-peptoid chimeras. Langmuir monolayers composed of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylglycerol (DPPG) were used to model cytoplasmic membranes of both Gram-positive and Gram-negative bacteria, while lipopolysaccharide Kdo2-lipid A ...[more]

PMID: 24878450

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Project description:The bacterial membrane represents an attractive target for the design of new antibiotics to combat widespread bacterial resistance. Understanding how antimicrobial peptides (AMPs) and other membrane-active agents attack membranes could facilitate the design of new, effective antimicrobials. Despite intense study of AMPs on model membranes, we do not know how well the mechanism of attack translates to real biological membranes. To that end, we have characterized the attack of AMPs on Escherichia coli cytoplasmic membranes and directly compared this action to model membranes. AMPs induce membrane permeability in E. coli spheroplasts or giant unilamellar vesicles (GUVs) under well-defined concentrations of AMPs and fluorescent molecules. The action of AMPs on spheroplasts is unique in producing an intracellular fluorescence intensity time curve that increases in a sigmoidal fashion to a steady state. This regular pattern is reproducible by melittin, LL37, and alamethicin but not by CCCP or daptomycin, agents known to cause ion leakage. Remarkably, a similar pattern was also reproduced in GUVs. Indeed the steady-state membrane permeability induced by AMPs is quantitatively the same in spheroplasts and GUVs. There are, however, interesting dissimilarities in details that reveal differences between bacterial and lipid membranes. Spheroplast membranes are permeabilized by a wide range of AMP concentrations to the same steady-state membrane permeability. In contrast, only a narrow range of AMP concentrations permeabilized GUVs to a steady state. Tension in GUVs also influences the action of AMPs, whereas the spheroplast membranes are tensionless. Despite these differences, our results provide a strong support for using model membranes to study the molecular interactions of AMPs with bacterial membranes. As far as we know, this is the first time the actions of AMPs, on bacterial membranes and on model membranes, have been directly and quantitatively compared.

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Guanidino groups greatly enhance the action of antimicrobial peptidomimetics against bacterial cytoplasmic membranes.

Publications

Guanidino groups greatly enhance the action of antimicrobial peptidomimetics against bacterial cytoplasmic membranes.

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