Wednesday, March 18
7:30 Registration and Morning Coffee
8:30 Chairperson’s Remarks
John Domagala, Ph.D., Senior Director, Research, IDSC
8:35 Where are the New Antibacterials?
John Domagala, Ph.D., Senior Director, Research, IDSC
The difficulties of antibacterial drug discovery will be probed qualitatively and quantitatively along with possible solutions. From screen to clinic attrition analysis of 100’s of projects will be discussed. Antibacterial chemical space, and the roles of molecular modeling and natural product screening will also be highlighted. Approaches to increase the odds of success will be described.
9:10 Structure-Based Drug Design Targeting Gram-Negative Infectious Disease
Graham Johnson, Ph.D., Chief Research Officer, Rib-X Pharmaceuticals
Using our computational tools and cumulative structural knowledge of how small molecules bind to the bacterial ribosome, we have designed and elaborated three completely novel series of antibiotics that show broad-based microbiological activity against serious Gram-negative pathogens. Because these are completely novel scaffolds that should not be affected by existing resistance mechanisms, these new leads offer promise for therapy in an area where multidrug resistance is a rapidly evolving problem. In this presentation we will describe these new structures and outline the approach that we have used to generate them.
9:45 Fragment Lead Identification at the Seattle Structural Genomics Center for Infectious Disease
Bart Staker, Ph.D., Associate Director, Protein Crystallography, deCode biostructures
The Seattle Structural Genomics Center for Infectious Disease (SSGCID) is a consortium of four institutions funded by NIAID to determine the structure of ~400 protein targets from NIAID Category A-C, as well as emerging and re-emerging infectious disease organisms over a period of five years. Annual selection of a small number of high-impact targets for fragment-based drug lead discovery is also ongoing using multiple biophysical techniques (NMR, SPR and crystallography), with the goal of completing two targets per year. SSGCID is also committed to providing structural genomics service to the research community and publicly disseminating all structure information and material resources generated as part of the NIAID contract.
10:20 Networking Coffee Break in Exhibit Hall
11:00 Discovery of the Pyrimidine Series of Antibacterial Agents through Structure-Guided Lead Discovery and Optimization
John Finn, Ph.D, Chief Scientific Officer, Trius Therapeutics
New classes of antibacterial agents that act by inhibition of novel targets are highly desired to combat bacterial resistance. Several groups have discovered antibacterial agents that target bacterial methionyl-tRNA synthetase but these compounds are limited in utility due to high serum-binding. We applied structure-based drug discovery tools to design a novel series of Gram-positive antibacterial agents that maintain their antibacterial activity in the presence of serum and are highly potent in vivo. In this presentation, we will describe our approach and how we overcame multiple problems that frustrated previous efforts.
11:35 Lantibiotics - A New of Antibiotics for Treatment of
Nosocomial Infections
Michael Dawson, Ph.D., Chief Scientific Officer, R&D, Novacta Biosystems, Ltd.
Lantibiotics are highly post-translationally modified peptides, many of which have antibacterial activity. Type A lantibiotics act by pore formation but type B lantibiotics bind lipid II and act as cell wall biosynthesis inhibitors. The type B lantibiotics are highly stable and drug-like in their properties. Novacta has developed a platform for manipulation of lantibiotic structure and activity using a combination of molecular biology and chemistry. A derivative of a natural lantibiotic has been selected as a drug candidate for treatment of Clostridium difficile infection and is undergoing formal preclinical development. Other programmes are addressing treatment and prophylaxis of nosocomial infections (MRSA, VRE) and surprisingly even therapy of Gram-negative infections.
12:10 Aeropath: An EU Consortium for Characterization and Exploitation of Novel Gram-Negative Drug Targets
William Hunter, Ph.D., Professor of Structural Biology, Division of Biological Chemistry and Drug Discovery, University of Dundee
An ambitious programme of multidisciplinary research has been initiated to advance understanding, at the molecular level, of fundamental aspects of the biology of Gram-negative bacteria. Our consortium seeks to exploit our discoveries to develop ligands and inhibitors (hit and lead compounds) with the potential to underpin early stage drug discovery. The research covers experimental validation of targets, biochemical and structural biology on these targets. The application of virtual screening, assessment of druggability, high-throughput screening, computational modelling and then design and modelling of ligands to enhance binding properties.
12:45 Lunch on Your Own
1:55 Chairperson’s Remarks
Urs Ochsner, Ph.D., Principle Scientist, Head of Microbiology, Replidyne, Inc.
2:00 Discovery & Development of Novel Targeted and Broad-Spectrum Antibacterials
Lloyd Czaplewski, Ph.D., Director of Research, Prolysis Ltd
The biology and medicinal chemistry of novel inhibitors of bacterial cell division and DNA supercoiling will be presented.
2:35 Development of Methionyl tRNA Synthetase Inhibitors against S. aureus and C. difficile Infections
Urs Ochsner, Ph.D., Principle Scientist, Head of Microbiology, Replidyne, Inc.
Fully synthetic diaryldiamine compounds that represent novel chemical entities have been optimized to target the methionyl tRNA synthetase of S. aureus and C. difficile. REP8839 has potent in vitro activity against clinically important Gram-positive bacteria including MRSA (MIC90=0.5 mcg/mL)and is evaluated as a topical agent for the treatment of skin infections. REP3123 has good activity against C. difficile (MIC90=1 mcg/mL) yet does not inhibit many of the beneficial species of the gut microbiome, and blocks toxin production and sporulation. An update is presented on the novel mode of action of these agents their microbiological profile and efficacy in animal models of infections.
3:10The Application of Whole Cell Screening Systems to Antibacterial Discovery
Scott D. Mills, Ph.D., Principle Scientist, Infection Discovery, AstraZeneca R & D
3:45 Networking Refreshment Break in Exhibit Hall
4:25 The Monobactam BAL30072: Responding to the Threat of Gram-negative Non-Fermentors
Malcolm Page, Head, Biology & Research, Basilea Pharmaceutica International, AG
BAL30072 is a novel, safe and cidal antibiotic of the monobactam class. BAL30072 is highly potent against resistant Gram-negative bacteria, in particular non-fermentors such as Pseudomonas, Acinetobacter and Stenotrophomonas. In vivo, BAL30072 shows efficacy in sepsis, pneumonia, urinary tract and thigh abscess rodent infection models.
5:00 The Problem of Multi-Drug Resistant Gram-Negative Bacteria, Why More Potent Classical Antibiotics are Not the Answer
Thomas Gootz, Ph.D., Thomas Gootz Consulting
Amid the recent emphasis on new products developed against methicillin-resistant Staphylococcus aureus, few new agents are available for the multidrug-resistant (MDR), Gram negatives Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii that are rapidly gaining ground as agents of serious nosocomial infections. Acinetobacter spp. historically have been associated with opportunistic infections that were rare and of rather modest severity; the last two decades have seen an increase in both the incidence and seriousness of A. baumannii infections, with the main targets being patients in intensive care units. Although this organism appears to have a predilection for the most vulnerable patients, community-acquired A. baumannii infections are increasingly cause for concern as well. The surge in both the incidence and severity of A. baumannii infections has paralleled the alarming resistance development it has demonstrated. P. aeuginosa has been a problematic pathogen in hospitals for over two decades. No new antibiotics today have demonstrated any significant improvement in activity against MDR strains from this species. Likewise, MDR strains of Klebsiella pneumoniae have become a global threat largely due to the rapid dissemination of Klebsiella Carbapenemase Genes (KPC) encoding carbapenemases that inactivate most all β-lactams. The rather plastic nature of the genomes of these three species has stymied efforts of Pharma to make improvements in classical antibiotics that would have meaningful utility against them. Their persistence in health-care facilities, inherent hardiness, and their resistance to antibiotics ensures that these three species will be formidable pathogens over the next decade. It is the highest challenge for large and small Pharma alike to design new approaches of both therapeutic and preventive strategies in order to regain control of these pathogens.
5:35 Development of Synthetic Mimetics of the Host Defense Proteins as Pan-Staphylococcal Antimicrobial Agents
R. Eric McAllister, M.D., D.Phil., Vice President, Clinical Development & Chief Medical Officer, PolyMedix, Inc.
A series of arylamide compounds that mimic structural properties of the antimicrobial peptides were found to have potent antibacterial activities and wide selectivity ratios versus mammalian cells. MIC90 values against 150 Staphylocoocal isolates with defined susceptibility phenotypes are 1 ug/ml for two lead compounds. The leads are highly efficacious in vivo in mouse thigh burden and peritonitis/sepsis models. One lead compound, PMX30063, is being developed as an IV antibiotic to treat Staphyloccocal infections including MRSA and is presently in Phase 1 human clinical trials.
6:10 End of Day