Design, Synthesis, and Biological Evaluation of Novel Anti-Biofilm Molecules Derived from the Oroidin Alkaloids

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Title: Design, Synthesis, and Biological Evaluation of Novel Anti-Biofilm Molecules Derived from the Oroidin Alkaloids
Author: Richards, Justin James
Advisors: Bruce Novak, Committee Member
alexander deiters, Committee Member
Christian Melander, Committee Chair
Daniel Comins, Committee Member
Abstract: Bacterial biofilms are a surface attached community of microorganisms that are protected by an extracellular matrix of biomolecules. Within a biofilm state, bacteria are more resistant to antibiotics and are inherently insensitive to antiseptics and basic host immune responses. Biofilm infections of indwelling medical devices are also of major concern, as once the device is colonized, infection is virtually impossible to eradicate. Given the prominence of biofilms in infectious diseases, there has been an increasing effort toward the development of small molecules that will modulate bacterial biofilm development and maintenance. This, coupled with the spread of multi-drug antibiotic resistance across many of these bacteria, has put a tremendous burden on the medical community to alleviate biofilm related problems. Herein the design, synthesis, and biological evaluation of small molecules derived from the oroidin class of marine natural products that both inhibit and disperse a number of medically relevant bacterial biofilms through a non-microbicidal mechanism is highlighted. This includes improvements to existing methodological approaches aimed toward the synthesis of these molecules in addition to the implementation of novel synthetic pathways which allow for the generation of diverse chemical libraries. Detailed structure-activity relationship (SAR) studies were performed with the ultimate goal of delineating which structural features of the analogues were essential for a biological response within the context of anti-biofilm activity. Preliminary toxicology studies also indicate that many of the analogues display non-cytotoxic properties, thus furthering hope for the use of these molecules in therapeutic biofilm remediation efforts.
Date: 2009-07-07
Degree: PhD
Discipline: Chemistry
URI: http://www.lib.ncsu.edu/resolver/1840.16/5829


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