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WEDNESDAY, APRIL 13
7:45 am Continental Breakfast Breakout Discussions
Topic 1: How Resistance will Shape the Antibacterial Drug Development Process
Moderator: Ursula Theuretzbacher, Ph.D., Founder, Center for Anti-Infective Agents (CEFAIA)
Topic 2: What’s New in Screening for Novel Compounds?
Moderator: Lynn L. Silver, Ph.D., Silver Consulting, LLC
• The state of natural product screening for antibacterials
• Status of whole cell phenotypic screening
• HTS screening: are poor chemical libraries the main problem?
8:55 Chairperson’s Opening Remarks
Scott Mills, Ph.D., Principal Scientist, Infection Discovery & Bioscience, AstraZeneca
9:00 Discovery of Novel Antibacterial Inhibitors of DNA Ligase: From Enzyme Inhibition to in vivo Efficacy
Scott Mills, Ph.D., Principal Scientist, Infection Discovery & Bioscience, AstraZeneca
Bacterial NAD+-dependent DNA ligase was evaluated for its potential as a broad-spectrum antibacterial target. A novel class of substituted adenosine analogs was discovered by target-based high throughput screening. The adenosine analogs inhibited DNA ligase activity from a broad spectrum of pathogenic bacteria. Antibacterial activity was observed for Gram-positive and Gram-negative pathogens, and was shown to be mediated by inhibition of DNA ligase. In vivo efficacy was demonstrated in murine infection models, thus validating DNA ligase as a target for antibacterial therapy.
9:30 High-Throughput Selection of New Antimicrobials with Random Sequence Peptide Microarrays
Valeriy Domenyuk, Ph.D., Center for Innovations in Medicine, The Biodesign Institute at Arizona State University
We report the use of 10,000 random sequences peptide microarray as a tool for the initial high-throughput selection of antimicrobial peptide-candidates interacting specifically with bacterial membranes. Developed hyperbranched polymer microarray surface chemistry and binding/competition assays allowed profiling entire bacterial cells and distinguishing strains E.coli O111:B4, Pseudomonas aeruginosa PAO-1, Staphylococcus aureus UAB637, Streptococcus mutans UAB147, and Bacilus subtilis 1A423. The combination of intracellular staining with outer membrane labeling facilitates distinguishing peptides that disrupt bacterial membranes and peptides that bind the bacterial cells without damage. Binding and antimicrobial activity of peptides selected from microarray were proven in solution phase. The linking of a binding peptides and a lytic peptide based on microarray profile resulted in a dual-function chimeric peptide with increased specificity and antimicrobial activity against Pseudomonas aeruginosa and Staphylococcus aureus.
10:00 Networking Coffee Break in the Exhibit Hall with Poster Viewing
11:00 ACHN-490, a Next-Generation Aminoglycoside
Ryan Cirz, Ph.D., Scientist II, Microbiology, Achaogen
11:30 New Drugs for Bad Bugs
Patrick Iversen, Ph.D., Senior Vice President, Research and Innovation, Research, AVI BioPharma
AVI’s proprietary adaptable platform chemistry, phosphorodiamidate morpholino oligomers (PMO), has significantly improved the stability, function, and bioavailability of antisense complexes (PMO bound to target RNA). The biological effects of PMOs are evident after intravenous, intraperitoneal, subcutaneous, intranasal, and transdermal administrations, because of intrinsic biodistribution and bioavailability characteristics of these compounds. The theoretical biological advantages of PMO are based on a non-enzymatic mechanism of action (neither RNase H nor RISC). The PMO do not result in “off-target” effects and as a result are highly sequence specific. The list of PMO-based compounds susceptible organisms evaluated to date includes the gram negative E. coli, B. multivorans, A. baumanii, S. typhimurium, N. gonorrhea, P. aeruginosa, K. pneumoniae and Y. pestis. A review of critical success factors in antibacterial drug discovery including susceptibility, mechanism of action, and efficacy in animal models selectivity, resistance, and evaluation of pharmacokinetic and toxicology features will be discussed.
12:00 pm End of Conference
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