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Title

A COMPRHENSIVE MECHANISTIC STUDY OF PEPTIDOMIMETICS ON MODEL MEMBRANE SYSTEMS

Creator

Bianchi, Christopher P.

Date

2014, 2014-12

Description

Peptidomimetics are a broad class of structural variant synthetic mimics of antimicrobial peptides (AMPs). AMPs are natural antibiotics found...
Show morePeptidomimetics are a broad class of structural variant synthetic mimics of antimicrobial peptides (AMPs). AMPs are natural antibiotics found in almost entirety throughout all living organisms. Although, AMPs were once thought of as promising therapeutics to combat infectious bacteria, key shortcomings such as low bioavailability, as well as high manufacturing costs have prevented them from reaching a clinical market. Peptidomimetics capitalize on the characteristics of AMPs thought to be responsible for their antibacterial activity, such as net cationic charge and amphiphilicity, while introducing key structural differences. The principal mode of antibacterial activity of AMPs is causing disruption to the bacteria cell membrane of both Gram-positive and Gram-negative bacteria types. The complexities of cell membranes with their various lipid molecule species and proteins makes it difficult to determine mechanistic details of AMPs. It is for this reason model membrane systems such as Langmuir monolayers and supported bilayers composed of the lipid species found in that of actual cell membrane are used. In the present work we have investigated the mechanism of action of different types of peptidomimetics such as N-substituted glycines (peptoids) and oligomers of acylated-lysines (OAKs) on model bacteria and cancer cell membrane systems using various experimental techniques, such as epifluorescence microscopy (EFM), atomic force microscopy (AFM), X-ray reflectivity, and grazing incidence X-ray diffraction (GIXD). From these studies structure function relationships can be obtained, which help aid in the design of new and more effective peptidomimetics. Through these investigations it was found that the substitution of hydrogen atoms for fluorine atoms in the phenyl side chains of cyclic peptoids increases antibacterial on both Gram-positive and Gram-negative model membrane systems, guanidino containing side chains compared to amino containing side chains in α-peptide-β-peptoid chimeras show greater activity on model membrane systems mimicking the cytoplasmic membrane of both Gram-positive and Gram negative bacteria. In addition, insights were gained on the anticancer mechanisms of the naturally occurring AMP magainin-2 and OAK C12K-7α8. The significance of the model membrane system being used cannot be overstated, when the overall arching goal is to bring these peptidomimetics to a clinical market. Thus, the biological relevance of the model membrane system is of great importance. It is this motivation that has lead our research group to develop a floating planar lipid bilayer that is bound to a lipid monolayer functionalized with polyethylene glycol, which to our knowledge has not been previously done. This system and the planar Langmuir monolayer that were used in this work are ideal systems for the use of high energy X-rays that are produced from synchrotron radiation facilities. From such measurements as X-ray reflectivity (XR) and grazing incidence X-ray diffraction (GIXD) molecular scale resolution of the peptidomimetic interactions with the model membrane systems can be achieved.
Ph.D. in Physics, December 2014
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