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Structure-activity relationships of antimicrobial peptide mimics

Posted on:2011-04-02Degree:Ph.DType:Dissertation
University:Illinois Institute of TechnologyCandidate:Ivankin, AndreyFull Text:PDF
GTID:1460390011472812Subject:Biophysics
Abstract/Summary:
Antimicrobial peptides (AMPs) are naturally occurring antibiotics found in essentially all living organisms. In the past two decades, AMPs have attracted considerable interest because of their potential therapeutic use as antibiotics, antivirals, and antitumoural drugs. However, there are a number of serious challenges on the way toward bringing AMPs onto the market which include their rapid in vivo degradation, high production costs, reduced activity in physiological conditions, etc. To overcome these problems and yet to capitalize on the immense potential of AMPs, extensive efforts to develop their non-natural mimics have been recently made.;A better understanding of the structure-activity relationships of AMPs is essential to the creation of a successful peptidomimetic compound. It has been widely accepted that AMPs kill pathogens by disrupting the cell membrane or invading the cytoplasm and inhibiting core metabolic functions. Thus, the pathogenic membrane plays a crucial role either as an immediate target or as a barrier that must be traversed.;Herein, we have investigated critical determinants in the interplay between membrane-active molecules (AMP mimics and viral peptides) and model bacterial or host cell membranes using constant-pressure insertion assays, epifluorescence microscopy (EFM), synchrotron X-ray reflectivity (XR) and grazing incident-angle X-ray diffraction (GIXD). The outer surface of a membrane was approximated by a planar lipid monolayer at the air-liquid interface, whose composition was modified in accordance with the cell being modelled.;To the best of our knowledge, we demonstrated for the first time at the molecular level that antimicrobial agents that mimic the structure of natural AMPs also imitate their mechanism of action. Strikingly, presented results strongly suggest that structural similarities to AMPs are not obligatory for potent and selective anti-infective activity of AMP mimics. Instead, a conformational flexibility of antimicrobial agent that is often missing in natural counterparts appears to be beneficial in penetration of bacterial cell wall barriers.;Another key player in the interplay between antimicrobials and biomembranes are lipids. Here it has been demonstrated on example of cholesterol that lipids can considerably affect both the structural organization of biomembrane and penetration properties of membrane-active molecules.;Overall, presented results advance current understanding of the mechanism of action of AMPs and their mimics on bacterial membranes and will no doubt aid in the rational design and optimization of non-natural mimics of antimicrobial peptides that will be effective against multidrug resistant bacteria and cancer cells. Nevertheless, future work is required to further understand the critical factors leading to potent anti-infective activity of antimicrobials.
Keywords/Search Tags:Antimicrobial, Amps, Activity, Mimics, Cell
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