Thursday, March 19
7:30 Breakfast Breakout Roundtable Discussions
Brainstorming discussion groups moderated by experts in the area. Attendees are invited to choose the topic according to their main interest, however, they may switch between roundtables. We emphasize that this roundtable discussion is intended for an interactive exchange among scientists and is not meant to be, in any way, a corporate or product discussion. Topics moderated:
Table 1: The challenge of gram-negative bacteria
Moderator: Thomas Gootz, Ph.D.
Table 2: the challenge of structure based design and how to deal with it
Moderator: John Finn, Ph.D., CSO, Trius Therapeutics
Table 3: choosing the right animal model
Moderator: Dario Lehoux, Ph.D., Director, In Vivo – Pharmacology, Targanta Therapeutics
8:30 Roundtable Feedback by Moderators
8:55 Chairperson’s Remarks
9:00 A Case Study: NXL101, a Type II Topoisomerase Inhibitor
Camille Pierres, Ph.D., Senior Scientist, Novexel S.A.
NXL101 is a representative of a new class of quinoline antibacterial agents which inhibit DNA gyrase and topoisomerase IV. NXL101 shows potent activity against Gram-positive bacteria, including methicillin- and fluoroquinolone-resistant strains. An overview of the discovery, pre-clinical and clinical aspects of the project will be described. This project is an example of medicinal chemistry work focussed on improving not only enzymatic and cellular target potencies, but also ADME and hERG properties. The benefit of monitoring ADME and hERG parameters early in discovery phase will be particularly discussed.
9:35 The Story of PZ-601 and Protez P
Luigi Xerri, Ph.D., Co-Founder, Chief Scientific Officer, Protez Pharmaceuticals, Inc.
10:10 Networking Coffee Break in Exhibit Hall
10:45
Clostridium Difficile-Associated Disease (CDAD): Using Animal Models to Accelerate the Discovery of Novel Antibacterial Strategies
Wangxue Chen, D.V.M., Ph.D., Senior Research Officer, Institute for Biological Sciences, National Research Council Canada
C. difficile infection is a serious concern in both hospital and secondary healthcare environments. The recent emergence of epidemic hypervirulent strains and the increasing ineffectiveness of current treatment strategies, particularly for patients with multiple recurrences, greatly emphasize the need for more effective treatments for severe and recurrent C. difficile-associated diseases (CDAD). In this regard, several new antibiotic and non-antibiotic treatments have been developed and some are currently under clinical evaluation for the treatment of CDAD. However, a major obstacle in the development of novel antibacterial agents for CDAD is the sporadic, although sometimes epidemic, occurrence of CDAD which renders appropriately designed clinical trials difficult. Thus, the evaluation of potential therapeutic agents for CDAD will rely heavily on preclinical studies in animal models. Unfortunately, despite their importance, the options for animal models of CDAD are very limited. In this presentation, I will discuss the current availability of small animal models for CDAD, the pros and cons of each animal model for the evaluation of antibacterial agents for CDAD, as well as their potential for accelerating the discovery of new generations of antibiotics and non-antibiotic agents for the management of CDAD.
11:20 Preclinical Evaluation of Oritavancin for the Treatment of Clostridium difficile Infection
Dario Lehoux, Ph.D., Director, In Vivo – Pharmacology, Targanta Therapeutics
Clostridium difficile infection (CDI) is the leading cause of nosocomial infectious diarrhea. Current treatments show serious limitations, including incomplete response and recurrence which underscore the need for new CDI treatment options. Oritavancin is a lipoglycopeptide with activity against gram positive bacteria, including drug-resistant pathogens, in particular against vancomycin resistant enterococci. Here, we report our evaluation of the potential of oritavancin for the treatment of CDI, including a demonstration of its activity against C. difficile, in planktonic or spore form, in an in vitro gut model. Also, in the well documented hamster model of CDI, oritavancin at 100 mg/kg provided 100% protection at 12 days post-infection whereas all vancomycin-treated animals had succumbed to infection by the same time.
11:55 Optimization of a Carbapenem/Beta-Lactamase Inhibitor Combination against Resistant Pseudomonas aeruginosa and Acinetobacter baumannii
John Buynak, Ph.D., Professor, Chemistry, Southern Methodist University
12:30 Lunch on Own or Luncheon Presentation (Opportunity Available)
1:55 Chairperson’s Remarks
2:00 Comparative Genome-Scale Metabolic Reconstruction and Flux Balance Analysis of Multiple Staphylococcus Aureus Genomes Identifies Novel
Anti-Microbial Drug Targets
Vinayak Kapatral, Ph.D., Vice President Business Development, Genomics, Integrated Genomics
Using Whole genome metaboilc reconstruction and FBA analysis, we have identified 70 single and 54 pairs of enzymes whose corresponding metabolic reactions were determined to be unconditionally essential for the growth. Of these, forty four single enzymes and ten enzyme pairs were common to all the thirteen S. aureus subspecies.
2:35 Bad Bugs, No Drugs: a Novel of Broad Spectrum Beta Lactamase Inhibitors
Jeffrey Besterman, Ph.D., Chief Scientific Officer, Methylgene
3:10 Networking Refreshment Break in Exhibit Hall
3:30 Bacterial Quorum Sensing: A New Target for Anti-Virulence Immunotherapy
Gunnar F. Kaufmann, Ph.D., Assistant Professor, The Kim D. Janda Laboratory, Department of Chemistry, The Scripps Research Institute
Cell-to-cell communication via the exchange of small molecules, termed “autoinducers”, is a widespread phenomenon among Gram-negative and -positive bacteria. This microbial intercellular signaling that synchronizes population-wide gene expression in a cell density-dependent manner has been coined “quorum sensing” (QS). Specifically, the initial discovery that Gram-negative bacteria employ non-peptide structures, namely N-acyl homoserine lactones, to globally regulate the production of secondary metabolites and proteins, initiated a new area in microbiological research. Subsequently, other quorum sensing systems and small signaling molecules have been identified. With the emergence of antibiotic-resistant bacterial strains, most prominently methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, new approaches for combating bacterial infections are urgently needed. Inhibition of QS results in attenuation of bacterial virulence rather than direct killing of the microbe. In my presentation, I will highlight current approaches to control bacterial virulence using an immunotherapeutic strategy that effectively quenches bacterial QS signaling.
4:05 Discovery of a New Antimicrobial Peptide Identified from a Deep Ocean Marine Bacteria Isolate
Michael Lawman, Ph.D., Director of Basic Research, Department of Pediatrics, St. Joseph’s Children’s Hospital of Tampa
Marine environments, historically have been underutilized in the search for new drugs and are only now being more fully exploited by interdisciplinary groups devoted solely to drug discovery research. Despite some limited progress in identifying new antimicrobial compounds, there are a limited number of marine-derived compounds that have been shown to be active against multiple drug resistance (MDR) bacteria associated with opportunistic infections in hospital environments. This present study has discovered several different antimicrobial activities associated with bacterial isolates from the sediment samples taken from the ocean bed located in the Atlantic Ocean off the Carolina coast of the United States. Thirteen bacterial isolates were recovered from the sediment samples four of which have antibacterial activity. The antibacterial activity has been shown to be a low molecular weight peptide (< 5 kDa). The report will discuss the biology of the compound, its stability, production and secretion.
4:45 End of Conference