Membrane active antimicrobials
Fig. 1. (A) Electron density profile ρ(x,y) of the 2-D unit cell for complexes formed by the specifically active AMO-2 and DOPG:DOPE = 20:80 lipid membranes confirm the inverted hexagonal structure. The regions of lowest electron density correspond to lipid chains. Circular ‘rims’ of high electron density surrounding ‘holes’ of intermediate density correspond to lipid head groups surrounding water channels which have a diameter of ~3.4nm. (B) A proposed model of the unit cell is shown. The white and green spheres represent headgroups of zero intrinsic curvature (ex. DOPG, DOPC) and negative intrinsic curvature lipids (ex. DOPE), respectively. AMOs are represented by blue spherocylinders embedded in the membrane.
Synthetic analogs of natural host defense antimicrobial peptides have recently demonstrated broad-spectrum antimicrobial activity. These antimicrobial molecules employ nonspecific interactions to target generic features common to membranes of many pathogenic species, and bacteria have not been able to evolve resistance to such antimicrobials to date. At present, the precise molecular mechanism of these synthetic antimicrobial molecules is not known. In our recent work, we systematically investigated interactions and self-assembly between lipid vesicles and a prototypical family of synthetic phenylene ethynylene antimicrobial oligomers with tunable activity profiles (inactive, specifically active, non-specifically active) using synchrotron small angle x-ray scattering. These synthetic molecules do not span the membrane and their mechanism is distinct from all major proposed models for antimicrobial peptides. The antibacterial activity of these synthetic mimics correlates with an induced topological transition of the target membranes, in which a regular hexagonal array of monodisperse 3-nm water channels is formed. Different molecules in this family require different minimum volume fractions of negative-curvature lipids in order to form this inverted hexagonal phase of pores, which in turn correlates with antimicrobial activity. We believe this is the key to the mechanism of specificity in these compound, since the negative-curvature lipid content of eukaryotic membranes is significantly lower than that of bacterial membranes.
At present, we are working on peptide-based antimicrobials, such as the β-sheet peptides (beta-defensins, theta-defensins, protegrins), and the lantibiotics (ex. cinnamycin).
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| n | AMO | MIC(ug/ml) | HC50 (ug/ml) | HC50/MIC | ||
| E. coli | B. subtilis | E. coli | B. subtilis | |||
| 1 | 1 | >100 | >100 | >100 | N/A | N/A |
| 2 | 2 | 0.8 | 1.7 | 75 | 93 | 44 |
| 3 | 3 | 1.6 | 3.2 | 3.2 | 2 | 1 |