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Title: The Development of Ageliferin Inspired Small Molecules as Antibiofilm and Antibacterial Agents against Multidrug Resistant Bacterial Pathogens
Authors: Huigens, Robert William III
Advisors: Dr. Christian Melander, Committee Chair
Dr. Reza Ghiladi, Committee Member
Dr. Bruce Novak, Committee Member
Dr. Daniel L. Comins, Committee Member
Keywords: CAGE
chemical library synthesis
anti-biofilm activity
biofilm dispersion agent
biofilm inhibitor
Issue Date: 22-Jul-2009
Degree: PhD
Discipline: Chemistry
Abstract: 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.
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