Browsing by Author "Christian Melander, Committee Chair"

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The Design and Synthesis of 2-Aminoimidazole Biofilm Modulators.
(2010-08-04) Reed, Catherine; Christian Melander, Committee Chair; Alexander Deiters, Committee Member; Reza Ghiladi, Committee Member
The Design, Synthesis and Biological Examination of Marine Natural Product Inspired Antibiofilm Agents and Antibiotics.
(2010-06-23) Rogers, Steven; Christian Melander, Committee Chair; Daniel Comins, Committee Member; Reza Ghiladi, Committee Member; Frank Edens, Committee Member; Bruce Novak, Committee Member
Design, Synthesis, and Biological Evaluation of Novel Anti-Biofilm Molecules Derived from the Oroidin Alkaloids
(2009-07-07) Richards, Justin James; Bruce Novak, Committee Member; alexander deiters, Committee Member; Christian Melander, Committee Chair; Daniel Comins, Committee Member
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.
Gold Nanocrystal Therapeutics: Treatment of Multidrug Resistant Pathogens and Disrupting Protein/Protein Interactions.
(2010-06-30) Kudgus, Rachel; Christian Melander, Committee Chair; David Shultz, Committee Member; Lin He, Committee Member; Elon Ison, Committee Member; Douglas Cullinan, Committee Member
Small Molecule Control over Biological Processes
(2010-04-05) Heinecke, Christine Loraine; Christian Melander, Committee Chair; David Shultz, Committee Member; Reza Ghiladi, Committee Member; Jonathan Lindsey, Committee Member
Myotonic Dystrophy Type 1 (DM1) is a multisystemic neuromuscular disorder characterized by a (CTG)n (n > 50) triplet repeat expansion in the 3â€™-UTR of the myotonic dystrophy protein kinase gene (DMPK). Transcription produces aberrant poly(CUG) expansions which sequester a family of alternative splicing regulators, the muscleblind proteins (MBNL1-3). In the absence of muscleblind, CUG-binding proteins mediate aberrant splicing leading to the disease pathology. We investigated cyclic peptides for their ability to disrupt a (CUG)54:MBNL1 interaction as a unified approach towards treating DM1. To this end, we performed a phage display selection using a cysteine constrained cyclic heptapeptide library against immobilized (CUG)54, which evolved four highly conserved cyclic peptides. In an effort to develop cellularly irreducible analogs of the cysteine constrained heptapeptides, we performed solid phase peptide synthesis substituting allyl glycine at the N- and C-terminal positions, which were subjected to ring closing metathesis. One of the selected peptides was shown to bind (CUG)54 and disrupt the (CUG)54:MBNL1 interaction characteristic of DM1 to a small extent. Kinamycin D is a potent antitumor antibiotic; however, its biological mode of action is poorly understood. In order to further elucidate the mechanism by which kinamycin D mediates DNA damage, we employed DNA sequencing gel electrophoresis. We have demonstrated that under reducing conditions, acidic media promotes enhanced DNA cleavage. Additionally, our results indicate that kinamycin D is capable of generating reactive oxygen species under acidic pH in the presence of a reducing agent and that DNA cleavage is dependent on trace iron and hydroxyl radicals. Bone biology and architecture are regulated by the interplay between osteoclasts and osteoblasts. Imbalances in this relationship, which favor osteoclastogenic activity are implicated in a variety of skeletal diseases. In an effort to target osteoclasts and inhibit osteoclastogenesis, we have synthesized 1,4-substituted triazole libraries. Qualitative analysis of osteoclast maturation when treated with our compounds indicates some members of our triazole libraries to be the most potent known inhibitors of osteoclastogenesis ever disclosed. Bacterial biofilm infections are implicated as the cause of many persistent and chronic infections due to antimicrobial resistance and virulence factors conferred by their protective extracellular matrices. Bordetella bronchiseptica is a gram-negative bacterial pathogen known to colonize the respiratory tracts of animals forming biofilms that are highly resistant to antimicrobial therapy. We synthesized and screened a library of 1,4-substituted triazoles for modulation of B. bronchiseptica biofilm formation. We identified one small molecule, which displayed agonistic activity towards B. bronchiseptica in multiple nutrient sources.