Studies of Molecular Mechanisms of Synthetic Antimicrobial Compounds UsingSum Frequency Generation Vibrational Spectroscopy.

[摘要] The rise in bacterial resistance to antibiotics has spurred a significant amount of research intended to find an alternative approach, one of the most promising being antimicrobial peptides (AMPs).AMPs exhibit diverse structures, broad-spectrum activity, and a unique interaction mechanism.However, AMPs are also expensive to synthesize or isolate, susceptible to proteolysis, and have poorly understood pharmacokinetics.As a result, synthetic antimicrobial compounds exhibiting similar activity to their natural predecessors have become attractive as potential antibiotics.In this thesis, guidelines for future rational design and development of antimicrobial compounds are developed through studies of synthetic antimicrobial compounds.First, antimicrobial arylamide oligomers, structured to mimic the inherent global amphiphilic structure of naturally-occurring AMPs are characterized, using both biological and spectroscopic analyses.The interaction mechanism of each oligomer is determined using bacterial, erythrocyte and mixed membrane models, and orientation of each active oligomer as it interacts with the bilayer is determined.Oligomers are shown to orient approximately parallel to the bilayer surface normal, cutting into the bilayer in a ;;molecular knife” style of interaction, showing these oligomers mimic the functionality of naturally-occurring AMPs.Second, antimicrobial random co-polymers containing varying lipophilic side chains are characterized using both biological and spectroscopic methods.Polymers with different lipophilic chains show vastly different interaction patterns, indicating the importance of the identity of the lipophilic chain, and providing insight into rational design considerations.Lipophilic groups structurally similar to membrane constituents are best able to effectively disrupt the lipid bilayer, and tuning amphiphilic balance can both help and hinder the polymer’s ability to interact with the bilayer.Finally, a random tri-polymer is coated onto a surface and characterized.Results indicate a strong tendency for surface dominance by lipophilic alkyl chains, with increasing surface coverage of those chains resulting in increased disorder both in terms of defects within the alkyl chain and orientation of the terminal methyl group.This disorder is attributable to steric hindrance, which may have significant implications for the surface’s antimicrobial character.Taken together, these studies provide a model for the rational design of synthetic antimicrobial compounds for a variety of applications.

[发布机构] University of Michigan

[效力级别] Antimicrobial Polymer

[关键词] Antimicrobial Oligomer;Antimicrobial Polymer;Sum Frequency Generation;Solid-supported Lipid Bilayer;Chemistry;Science;Chemistry