Browsing by Author "Dr. Christian Melander, Committee Chair"

Filter results by typing the first few letters
Now showing 1 - 3 of 3
  • No Thumbnail Available
    The Development of Ageliferin Inspired Small Molecules as Antibiofilm and Antibacterial Agents against Multidrug Resistant Bacterial Pathogens
    (2009-07-22) Huigens, Robert William III; Dr. Christian Melander, Committee Chair; Dr. Reza Ghiladi, Committee Member; Dr. Bruce Novak, Committee Member; Dr. Daniel L. Comins, Committee Member
    ABSTRACT HUIGENS III, ROBERT WILLIAM. The Development of Ageliferin Inspired Small Molecules as Antibiofilm and Antibacterial Agents against Multidrug Resistant Bacterial Pathogens. (Under the direction of Dr. Christian Melander.) The development of ageliferin inspired small molecules is described herein. These analogues collectively demonstrated non-toxic biofilm inhibition, biofilm dispersion activity and antibiotic activity. Biofilm-mediated infections pose a serious threat to due to increased drug-resistance to antibiotics and host immune responses. TAGE and CAGE were the first synthetic 2-aminoimidazoles to demonstrate the ability to inhibit biofilm formation against Pseudomonas aeruginosa. In growth curve analysis, TAGE demonstrated less toxicity towards planktonic P. aeruginosa than CAGE. These two small molecules also dispersed preformed PAO1 and PA14 biofilms. TAGE was also evaluated in confocal microscopy experiments and demonstrated the ability to disperse PAO1:gfp biofilms under continuous flow conditions as well as demonstrating non-toxic effects towards bacterial cells within a biofilm in DEAD/LIVE staining. BromoTAGE and DibromoTAGE, two TAGE-Pyrrole analogues, demonstrated increased biofilm inhibition compared to TAGE or CAGE against P. aeruginosa strains. These analogues were also active against Acinetobacter baumannii and Staphylococcus aureus biofilm formation. The parent structure, TAGE, was found to be inactive against these strains of bacteria. Although these pyrrole analogues of TAGE were very effective in biofilm inhibition screens, they demonstrated little activity in biofilm dispersion activity. A 21-membered library of TAGE-Triazoles was then synthesized and screened for biofilm inhibition activity. The majority of this library demonstrated non-toxic, biofilm inhibition against A. baumannii. Various members from this collection of TAGE-Triazoles were also active against S. aureus and P. aeruginosa in biofilm inhibition assays. Dibromopyrrole TAGE-Triazole demonstrated very potent biofilm inhibition activity against S. aureus (IC50 = 141 ± 28 nM). A diverse library of 2-aminobenzimidazoles (2ABIs) was synthesized and found to possess impressive antibiotic activity against several strains of multidrug-resistant bacteria. Methicillin-resistant Staphylococcus aureus was unable to demonstrate resistance against the active members from this library. The active 2-aminobenzimidazoles also demonstrated promising antibiotic activity against several clinical isolates of A. baumannii. Active 2ABIs also demonstrated broad spectrum antibiotic activity against several other bacteria.
  • No Thumbnail Available
    Evolution of Cyclic Peptide Scaffolds to Target Nucleic Acids
    (2009-04-23) Burns, Virginia Abigail; Dr. Christian Melander, Committee Chair; Dr. Reza Ghiladi, Committee Member; Dr. John Cavanagh, Committee Member; Dr. Tatyana Smirnova, Committee Member
    Given the great strides that have taken place over the past few decades in our understanding of nucleic acid’s role in cellular processes, it has become abundantly clear that DNA and RNA can provide a great tool and target for drug development. The human genome project has provided a major impetus in identifying human genes implicated in diseases and has opened the door to new possibilities with DNA-based therapeutics. Further developments in transcriptomics and proteomics will provide an additional momentum for the advancement of therapeutics by supplying novel targets for drug design, screening, and selection. As new discoveries are made and our knowledge of nucleic acid’s role in life processes is expanding, the area of chemistry focused on learning how to target and exploit these nucleic acids for control of their relative processes is also expanding. New strategies to develop molecules that can both identify DNA or RNA targets and modulate their activity are of great interest to medicinal chemistry. The goal of this research was to delineate an efficient approach to targeting nucleic acids that yields cell permeable, biologically stable molecules that can be exploited in vivo applications. Herein describes our approach which utilizes cyclic peptide phage display for the evolution of novel cyclic peptide scaffolds that target a given oligonucleotide. Evolved scaffolds are then tested in vitro as discrete entities to assess their binding capabilities. Given that the phage display scaffolds employ a disulfide linker for cyclization, alternative redox stable macrocylic linkers were developed and synthesized. Second and third generation analogues were subsequently assessed for the retention of the desired binding activity. The details of this pragmatic approach were developed using the bTAR RNA oligo as a model system. Results indicated that not only could we evolve bTAR binders form a pool of 1.2 billion possible scaffolds in a relatively short time, but that these scaffolds bound with affinities in the low micromolar range when tested as discrete entities. We also successful in developing an alternative dicarbon macrocyclic linker to yield redox stable analogues. Subsequent testing of the analogue scaffolds indicated the retention of the desired binding properties.
  • No Thumbnail Available
    Small Molecule Control of Biological Function
    (2008-08-27) Ballard, Thomas Eric Jr.; Dr. Christian Melander, Committee Chair; Dr. Bruce Novak, Committee Member; Dr. Daniel Comins, Committee Member; Dr. David Shultz, Committee Member