Wednesday, April 23, 2008
7:30 Registration and Morning Coffee
8:25 Chairperson’s Remarks
8:30 Addressing the Bacterial Entry Conundrum
Lynne L. Silver, Ph.D., LL Silver Consulting, LLC
One of the major obstacles to design and optimization of antibacterial agents is the requirement that small mole-cules get to the site of their targets, which is often the bacterial cytoplasm. How to confer properties allowing or promoting bacterial entry has not been systematically addressed. This talk will cover some research approaches which may approach this problem.
9:00 Innate Defense Regulation - a Novel Strategy to Counter Infection and Inflammation
John North, Ph.D., President & CEO, Research & Development, Inimex Pharmaceuticals Inc.
Innate Defense Regulator (IDR) treatment reduces bacterial colonization and improves survival against a broad spectrum of gram positive and gram negative organisms, irrespective of antibiotic resistance, while suppressing the bacterially-induced inflammatory response. IDRs act downstream of TLRs to modulate the innate defense response and offer a novel strategy to counter infectious disease without inducing resistance.
9:30 Phage Enzymes to Conquer Resistance – Using Natures Defenses
Stefan Miller, Ph.D., CSO, Profos, AG
10:00 Networking Coffee Break, Poster and Exhibit Viewing
NATURAL PRODUCT–BASED SCREENING
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10:45 AMR-BAC-XXX a Novel Antibiotic Derived From Stringent Screening of Natural Product Extracts
Grant Carr, Director, Lead Discovery, AMRI
The presentation will use one or more of the leads identified by the AMRI antibacterial program to demonstrate: The effectiveness of employing multi-drug resistant pathogenic bacteria to stringently screen natural product ex-tract libraries for new leads; How improvements in Natural Product Discovery now allow the routine identification of highly potent, low abundance actives from complex natural product samples and their exploitation for the generation of semi-synthetics. The presentation will be content rich providing details of the strategies used by AMRI to find antibacterial leads and their in vitro and in vivo biological activities.
11:15 Fighting Gram-Negative Infections: Challenges, Strategies and Clinical Update
Olga Lomovskaya, Ph.D., Senior Director of Biology, Mpex Pharmaceuticals, Inc.
11:45 Accelerated De-Replication Strategies and Database Support for Natural Product-Based Screening Projects
Thomas Henkel, Ph.D., C.E.O. InterMed Discovery, GmbH
InterMed Discovery (IMD), is dedicated to the discovery and development of innovative products for the Life Sci-ence industry, based on natural products (NPs).Among other assets, IMD disposes of one of the world-wide larg-est and most diverse sample libraries, including the world-wide largest pool of pure NPs, a Bioprofiling™ database comprising data from over 100 HTS assays, an expert system (NPsilico™), comprising information on all pub-lished chemical structures of NPs and the corresponding biological sources. Our talk will focus on IMD’s strategy to optimise the lead finding process in screening for novel antimicrobial lead compounds, with emphasis on mi-crobial sources. The rapid identification of iterature-known compounds without need for an authentic reference using a proprietary NMR- and MS-based de-replication strategy will be exemplified.
12:15 Lunch on Your Own
(Luncheon Workshop Sponsorship Available)
1:40 Chairperson’s Remarks
APPROACHES BY STRUCTURE, BIOINFORMATICS AND MODELS
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1:45 Structural and Chemogenomics Approaches to Antibacterials
Ruben Abagyan, Professor, Molecular Biology, The Scripps Research Institute
A comprehensive review and analysis of three dimensional structures of the antibacterial and antimalarial pro-teins and drug targets is presented. All the structures and ligand complexes are classified into families and superimposed by their pockets. The resulting panel of pockets, superimposed ligands allowed to formulated criteria of an ideal target from the structural and bioinformatic point of view. The recent advances in ligand docking, virtual screening and induced fit in conjunction with chemogenomics and binding data for human receptors lead to fast de novo identification of leads and their optimization.
2:15 Antimicrobial Lead Discovery via Metabolic Network Analysis, Homology Search, Virtual Screening and Computational Chemistry
Zoltan Oltvai, Associate Professor, Pathology, University of Pittsburgh
Advances in network biology and computational protein modeling and chemistry have the potential to revolutionize drug discovery by combining system-level identification of drug targets with the recognition of molecules capable of modulating their activity. To apply this approach to the development of novel antibiotics we set out to identify potential broad-spectrum antibiotic targets by comparing the metabolic networks of the bacteria, Escher-ichia coli, Helicobacter pylori, and Staphylococcus aureus. Of the catalytic enzymes of shared essential core reactions with consistently lethal deletion phenotype in E. coli we focused on Malonyl-CoA:acyl carrier protein transa-cylase (MCAT) that displayed a high level of sequence and structural conservation within prokaryotes. We predicted several potential inhibitors of E. coli MCAT through virtual screening of a small-molecule chemical library and by synthesizing novel compounds designed to act against the active site of the enzyme. Our results on their effect on blocking MCAT activity in vitro and prokaryotic cell viability in vivo will be presented.
2:45 Modeling the Clinical Relationships between Antibiotic PK, PD, PE, Efficacy and Bacterial Resistance to Establish Proof of Principle Early in Clinical Trials for Antibiotic Development
Jerome J. Schentag, PharmD, Professor of Pharmaceutical Sciences and Pharmacy, University at Buffalo School of Pharmacy and Pharmaceutical Sciences
Our studies demonstrate that calculations of AUIC can be used to prospectively target regimens to improve the chances of cure with nosocomial pneumonia and other serious infections. These procedures can be easily added to phase II and III dose-finding trials, and the reward is a measurable increase in the information value of the trials, arrival at the precise dose, and a good correlation between microbial effect and clinical outcome in the patients treated. Such parameters are useful to characterize either single agents or combination therapy, and in fact may be the only way to clinically demonstrate additivity and even synergy in the course of clinical trials. Finally, resistance can be predicted, once the relationship between PK/PD and bacteriostatic action is identified in the human trials.
3:15 Networking Refreshment Break, Poster and Exhibit Viewing
4:00 Mouse Models of Acinetobacter-Associated Pneumonia
Wangxue Chen, Ph.D., Senior Research Officer, Institute for Biological Sciences, National Research Council Canada
Acinetobacter baumannii infection has emerged as a major cause of both community-associated and nosocomial infections worldwide during the last decade. The overall 30-day mortality of Acinetobacter infection can be as high as 50%, with the respiratory tract being an important portal of entry. Moreover, A. baumannii infections have become increasingly difficult to treat because of its rapid development of resistance to multiple antibiotics. To facilitate the development and evaluation of new generations of pharmaceutics and immunotherapeutics for this pathogen, we have recently refined and comprehensively characterized the mouse model of respiratory A. baumannii infection. The mouse model mimics many aspects of human A. baumannii-associated pneumonia and can be used for the development and evaluation of potential pharmaceutics and mmunotherapeutics for the clini-cal management of respiratory A. baumannii infection. By using transgenic mice and cellular, molecular, histo-pathological and immunological approaches, we have identified several key host factors that play a crucial role in host defense against respiratory infection with this pathogen. This information will be useful for the rational se-lection of the most appropriate mouse models for anti-Acinetobacter therapeutics testing and facilitate the future development of new pharmaceutics and immunotherapeutics for this important pathogen.
4:30 Fighting Gram-Positive Bacteria
Hans-Henrik Kristensen, Ph.D., Senior Manager, Anti-infective Discovery, Novozymes A/S
- In vitro efficacy data (spectrum and potency)
- Efficacy in various animal models of infection (thigh infection model, granuloma pouch, endocarditis, sepsis, pneumonia, meningitis)
- PK-PD parameters for staphylococci and streptococci and prospects for human dosing regimen
- Molecular mechanism of action of plectasin
- Recombinant cGMP production process (production strain and purification)
- pre-clinical tox-safety program
FUNDING AND COLLABORATION STRATEGIES
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5:00 Leveraging US Government Dollars to Support a Commercial Product Pipeline
Jennifer Hannesschlager, Ph.D., Senior Advisor, Government Contracts, McKenna Long & Aldridge LLP
The increased and often inappropriate use of antibiotics has resulted in the selection of drug-resistant organisms and the emergence of infections that are difficult to treat. This is a growing problem, and researchers are responding with a variety of strategies including promotion of the rational use of antimicrobials, surveillance, infection control, and basic and applied research in areas such as microbial pathogenesis, diagnostics, new drugs, and novel therapies. Antimicrobial resistant pathogens were recently added to the NIAID/NIH Category C priority biodefense pathogens list. A broad consensus has emerged that decreasing the incidence of infections resistant to antimicrobials will require the cooperation of many individuals and organizations worldwide, including local, state and territorial health departments; U.S. federal agencies (CDC, NIH, DoD, FDA); professional and non-profit organizations; industry; and academia.
5:30 End of Day One