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Antibacterial Drug Development
1日目 | 2日目 4月17日, 火曜日 7:00 am Registration and Morning Coffee 8:00 Chairperson’s Opening Remarks
GYRASE/ TOPOISOMERASE INHIBITORS 8:50 Dual-Targeting DNA Supercoiling Inhibitors for the Treatment of Bacterial Infections Jim Palmer, Ph.D., Director, Drug Discovery, Research, Biota Holdings, Ltd. The emergence of new resistant strains of pathogenic bacteria presents an increasingly serious challenge to global health. We have identified a series of potent bacterial DNA gyrase/topoisomerase type IV inhibitors with a novel mechanism of action distinct from fluoroquinolone-based drugs. Advanced members of this series are well tolerated, and demonstrate class-leading intravenous and oral efficacy. 9:20 The Discovery of Potent, Dual Targeting Pyrrolopyrimidine Inhibitors of Bacterial DNA Gyrase B and Topoisomerase IV with Broad Spectrum Antibacterial Activity John Finn, Ph.D., CSO, R&D, Trius Therapeutics To combat antibacterial drug resistance, we are focused on discovering new antibacterial agents that work via novel mechanisms of action. To reduce emergence of resistance against these new antibacterial agents, we have used structure-based drug design to discover agents that target two essential bacterial targets: bacterial DNA gyrase B (GyrB) and topoisomerase IV (ParE). While these targets have been utilized in other antibacterial discovery programs, to date, no clinical compounds have emerged and spectrum of the compounds has been limited mainly to gram-positive bacteria. This presentation will detail our efforts leading to the pyrrolopyrimidine series: the first series of GyrB/ParE antibacterial agents that have an expanded antibacterial spectrum that includes important gram-negative pathogens. 9:50 Networking Coffee Break
TARGETING MRSA 10:15 Microbiological and Pharmacodynamic Interactions of Avibactam with the Anti-MRSA Cephalosporin Ceftaroline Ian Critchley, Ph.D., Vice President, Microbiology, Cerexa, Inc. Ceftaroline fosamil (Teflaro™) is a cephalosporin that was approved in the US in late 2010 for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP). Although ceftaroline is active against resistant gram-positive pathogens such as MRSA its activity against enteric gram-negative organisms is limited to non-ESBL-producing organisms. Avibactam is a novel non-β-lactam β-lactamase inhibitor that inhibits Ambler class A and C β-lactamases, that in combination with ceftaroline, extends its antibacterial activity against AmpC and ESBL-producing Enterobacteriaceae. This talk will summarize the microbiological properties of ceftaroline-avibactam and the studies conducted to date to understand and optimize the pharmacodynamic interactions of avibactam with ceftaroline that result in optimal bacterial killing with reduced propensity for resistance development. 10:45 Identification of Novel Drug Targets by Exploitation of Indel-Based Structural Differences in Highly Conserved Proteins: Pyruvate Kinase as a Test Case Roya Zoraghi, Ph.D., Research Scientist and Director of Screening, Indel Therapeutics Historically, antimicrobial drug development has been focused on targets found uniquely in pathogens, while avoiding proteins conserved between host and pathogen. However, recent discoveries have shown that many of these conserved proteins can be selectively targeted in the pathogen by exploiting indel-based sequence differences. This approach has the potential to develop into a platform technology that can be applied to selectively target highly conserved microbial proteins. LEAD DEVELOPMENTS 11:15 Artilysins: Antibacterial Enzymes that Attack Bacterial Surface Structures Stefan Miller, Ph.D., CEO, Lisando GmbH 11:45 Lunch on Your Own 1:25 Chairperson’s Remarks David Harper, Ph.D., CSO, AmpliPhi 1:30 Safe Drugs to Kill Bad Bugs — Evolva´s Novel Topoisomerase Inhibitors Jutta Heim, Ph.D., Professor, Biotechnology; CSO, Discovery, Evolva SA Evolva has discovered a new series of potent antibiotics, called 2-pyridones, which are chemically bioisosteres of quinolones. Like quinolones, our 2-pyridone EV-035 series are inhibitors of bacterial topoisomerases IIA BUT retain activity on mutated, quinolone-resistant bacteria by binding to a different site on the target enzyme. 4 members of the EV-035 series were fully profiled and exhibit the following characteristics: • Broad spectrum of activity, covering all Gram+ and Gram- pathogens tested • Active on multidrug- and quinolone resistant pathogens • Low propensity of resistance development in E. coli and S. aureus • Binding to a different site in the QRDR of gyrase than marketed quinolones • High aqueous solubility and high oral bioavailability • Favourable ADME-tox profile • Oral in vivo efficacy in mouse thigh models of MRSA and E. coli infections Those features make Evolva´s EV-035 a very promising candidate for further pre-clinical and clinical examination. 2:00 Bacteriophages as Antibacterial Agents David Harper, Ph.D., CSO, AmpliPhi Bacteriophages are viruses that infect and can then destroy their bacterial targets, amplifying themselves in the process. They are able to destroy antibiotic-resistant bacteria, even in biofilms. Driven by the crisis of antibiotic resistance, modern clinical trials are now under way. Results of the first phase II clinical trial of the efficacy of a bacteriophage therapeutic were published in 2009. This, together with other work has shown the potential of bacteriophages as a novel antibiotic approach. Sponsored by Roman Kombarov, Ph.D., Project Manager, ASINEX The creation of innovative chemotypes is a great challenge in anti bacterial drug discovery. Via our “Inverse Medchem” Approach, we show our proprietary platform for antibacterial design based on synthetic natural product-like molecules. This method allows for clogP and solubility control by using hydrophilic scaffolds, suitable for attaching multiple lipophilic or hydrophilic substituents. The scaffolds contain elements inherent to antibacterials such as tepenoids, glycomimetics & macrocycles which are often lacking in traditional screening libraries. 3:00 Selected Oral Poster Presentation 3:15 Networking Refreshment Break in Exhibit Hall with Poster Viewing 4:00 PK/PD and Emergence of Resistance Ursula Theuretzbacher, Ph.D., Center for Anti-Infective Agents (CEFAIA) With antibiotic usage emergence of resistance is unavoidable. However, several factors in the drug development process can be adjusted to reduce the risk of rapid emergence of resistance in clinical settings. During drug development, PK/PD models are appropriate tools for mitigating the risk of resistance. 4:30 Harnessing the Power of Transposon Mutagenesis for Antibacterial Target Identification Tim Meredith, Ph.D., Infectious Disease Division, Novartis Institute for Biomedical Research (NIBR) Determining the mechanism of action of bacterial growth inhibitors can be a formidable challenge in the development of antibacterial therapies. To help address this bottleneck, we developed a robust transposon mutagenesis system using a suite of outward facing promoters to generate a comprehensive range of expression genotypes in Staphylococcus aureus from which to select compound resistant transposants. Using this approach, an inhibitor’s molecular target, route of cellular entry, efflux susceptibility, and other off-target resistance mechanisms can be rapidly identified in a single experiment. 5:00 LTX-109, an Antimicrobial Peptide in a Small Molecule Package John S. Mjøen Svendsen, Ph.D., Director, Discovery Research, Lytix Biopharma AS Antimicrobial peptides are almost immune to resistance development, but hasn't seen much clinical use due to an array of pharmacological hurdles. LTX-109 is the result of extensive medicinal chemistry research on antimicrobial peptides, and represents a first member in a new class antimicrobials; synthetic antimicrobial peptidomimetics (SAMP). The talk will highlight the discovery of SAMP's and present the first phase 2a clinical results of LTX-109. 5:30 Networking Reception in the Exhibit Hall with Poster Viewing 6:30 End of Day |
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