Thursday, April 24, 2008
8:00 Morning Coffee
(Breakfast Workshop Sponsorship Available)
8:25 Chairperson’s Remarks
8:30 Case Study:
Oritavancin: The Discovery and Development of a Novel Lipoglycopeptide Antibiotic
Greg Moeck, Ph.D., Director, Biology, Targanta Therapeutics
Oritavancin is a late-stage, semi-synthetic lipoglycopeptide antibiotic having excellent activity against gram-positive bacteria including MRSA, VMRSA, VISA, VSE and VRE. This presentation will include the following: (i.) rationale and results of the natural products and synthetic chemistry efforts pursued to identify a lipoglycopeptide agent effective against vancomycin-resistant gram-positive bacteria, (ii.) description of approaches used to identify and dissect antibacterial activity and in vivo behavior of oritavancin, and (iii.) description of mechanism of action studies that explain the unique antibacterial activity against antibiotic-resistant bacteria.
9:00 Beta-Lactamase Inhibitors: Challenge and Promises
Robert Bonomo, M.D., Associate Professor of Medicine, Pharmacology, Molecular Biology and Microbiology, Case Western Reserve University School of Medicine; Section Chief of Infectious Diseases at the Louis Stokes Cleve-land Veterans Affairs Medical Center
Beta-Lactamases represent the greatest threat to successful beta-lactam therapy for serious Gram negative infections. The increasing number and diversity of beta-lactamases makes the quest for a “universal” beta-lactamase inhibitor an elusive goal. However, a carefully designed strategy that selectivley inhibits key beta-lactamases can offer significnat hope.
9:30 Novel Beta-Lactams against Current and Emerging Superbugs
Jutta Heim, Professor, CSO, Research, Basilea Pharmaceutica, Ltd.
Re-engineering of the clinically validated and widely used class of beta-lactam antibiotics, can be considered as one of the strategies to develop novel antibiotics overcoming resistance. Ceftobiprole, an anti-MRSA, broad spectrum cephalosporin, will be discussed as potent inhibitor of PBP2’, the protein responsible for MRSA. A novel combination of a monobactam together with beta-lactamase inhibitors, eg BAL30376, will be introduced as potent novel antibiotic covering a majority of treatment-resistant Gram-negative pathogens.
10:00 Coffee Break, Poster and Exhibit Viewing
IDENTIFYING NOVEL TARGETS
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10:45 Genome-Wide Identification of Antibacterial Combination Therapy Targets
Colin Manoil, Professor, Genome Sciences, University of Washington
A genome-wide approach to identifying antibacterial combination therapy targets will be presented. The ap-proach consists of screening comprehensive sequence-defined transposon mutant libraries of bacterial pathogens for strains hypersensitive to an established antibiotic. The corresponding gene products define potential targets for therapy with the established drug. The approach was employed to identify P. aeruginosa functions whose inhibition could enhance the clinical efficacy of the aminoglycoside tobramycin. A two-component regulator was identified whose absence markedly enhanced the aminoglycoside sensitivity of the reference strain and several resistant clinical isolates, as well as cells grown on laboratory medium and in biofilms. The regulator thus represents a candidate target for drug development for combination therapy with aminoglycosides.
11:15 Discovering Novel Antibiotics: Will Genomics Play a Revolutionary or Evolutionary Role?
Thomas J. Dougherty, Ph.D., Senior Principle Scientist, AstraZeneca R&D
Antibiotic discovery in the 1940-60’s era discovered most of the current classes of antibiotics using empirical screening methods. The impact of antibiotic use since that period has been a marked shift in the ecology of microbial populations, with widespread dissemination of resistance determinants. Faced with the resulting diminished efficacy of established classes, searches for new chemotypes were launched. While some notable success (e.g. linezolid) was achieved, by and large the results to date have been to a great degree disappointing. Paradoxically, this comes at a time in which the technical advances of the past decade in bacterial genetics, genomics, and physiology have described microbial cell systems in unprecedented detail. This presentation will focus on several key questions: why hasn’t the impact of this knowledge translated into effective antibiotic discovery programs to date? What might be some productive approaches to employing the various –omics technologies in a more effective way for antibiotic discovery? What do past antibiotic classes inform us about other key parameters in the antibiotic discovery process which need to be considerations in identifying potentially new lead matter?
11:45 The Identification & Lead Optimization of REP3123: A New Agent for CDAD?
Joe Guiles, Ph. D., Executive Director, Chemistry, Replidyne Inc.
The diaryldiamines are a new class of antibacterial agents currently in clinical development. They inhibit me-thionyl t-RNA synthetase (MetRS), which prevents protein synthesis and arrests the growth of bacteria cells. While screening our internal collection of diaryldiamines we discovered that some members of this class possess moderate activity against Clostridium difficile. Clostridium difficile is an anaerobe whose presence in the lower GI may lead to a particularly debilitating clinical condition, Clostridium difficile associated disease (CDAD). A lead optimization program identified a novel antibacterial agent, REP3123, that has an in vitro and in vivo microbio-logical profile that is competitive with antibiotics currently used to treat CDAD patients.
12:15 Lunch on Your Own
(Luncheon Workshop Sponsorship Available)
THE CHALLENGE OF SELECTING NOVEL THERAPEUTICS
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1:40 Chairperson’s Remarks
1:45 Using Structure-Based Discovery to Define Novel Macrolide Antibiotics Targeting the 50S Ribosomal Subunit
Graham Johnson, Ph.D., Chief Research Officer, Discovery, Rib-X Pharmaceuticals Inc.
Merging our proprietary high resolution X-ray structural knowledge of the bacterial ribosome with customized computational tools and targeted synthetic chemistry, Rib-X has developed a detailed molecular understanding of how and where the currently available antibiotics bind to and inhibit the function of the 50S ribosomal subunit. From this extensive dataset we have defined key regions within the ribosome which we have termed ribofunctional loci within which the binding of small molecules will interfere with ribosome function. In this presentation we will illustrate the application of these important ribosome structures to new antibiotic design that overcomes key resistance mechanisms. In particular we will outline the strategy and structure-based drug design methodologies that Rib-X has used to identify and refine a new family of macrolide-based antibiotics with efficacy against both community and hospital MRSA.
2:15 The Importance of the Evaluation of Resistance Rates when Selecting Novel Therapeutics
Karen M. Overbye, Ph.D., Research Fellow, Department of Infectious
Disease, Merck Research Laboratory
There are multiple hurdles for the discovery and development of a novel therapeutic agent. A low MIC against targeted pathogens is only one component. A low rate of pathogen resistance to any new therapeutic agent is crucial to a successful drug. Studies on drug resistance development to single and multiple drug targets will be discussed.
2:45 Networking Coffee Break, Poster and Exhibit Viewing
3:30 Tales About Surrogate Strains for Drug Screening
Herbert Schweizer, Professor, Microbiology, Immunology and Pathology, Colorado State University
Whole cell screening is often an important step in the drug discovery process, either during primary or secondary screens. During an attempt to set up screens for Burkholderia efflux pump inhibitors in a surrogate Pseudomonas aeruginosa host we discovered that expression of some pumps in P. aeruginosa strains yielded different pheno-types as compared to a surrogate Burkholderia strain or the source strain. For example, two pumps conferred aminoglycoside resistance in a surrogate B. thailandensis, but not a P. aeruginosa strain. These findings highlight the importance of choosing strains for whole cell screening or susceptibility testing wisely. Otherwise, drugs in-tended for the bacterium of choice may be missed.
4:00 The Looming Threat of Gram-Negative Infections
Nafsika Georgopapadakou, Ph.D., Vice President, Preclinical Research, Novabay Pharmaceuticals, Inc
Gram-negative bacteria cause a variety of nosocomial and community-acquired infections and include some of the most deadly pathogens. As a result, their resistance to antibiotics has profound clinical implications. Indeed, four gram-negative organisms - Escherichia coli, Klebsiella sp., Acinetobacter baumanii and Pseudomonas aerugi-nosa - are in the IDSA target list. The major antibiotic classes currently in use for gram-negative bacterial infec-tions are the beta-lactams, quinolones, aminoglycosides, tetracyclines, and sulfonamides. Resistance to beta-lactams is relatively common and involves mainly serine;-lactamases: inducible, typically chromosomal (class C) as well as constitutive, typically plasmid-mediated, extended spectrum (classes A and D). Integron-borne beta-lactamases (classes A, B, and D) occur in gram-negative species together with non-beta-lactam resistance genes giving rise to multi-drug resistant bacteria. They pose a threat, particularly in the hospital environment, as non-β-lactam agents may select potent beta-lactamases through integron-mediated resistance. Resistance to quinolones is associated with changes in the target DNA gyrase (chromosome encoded) or target protection by the proteins QnrA, QnrB, and QnrS (plasmid encoded) and affects quinolones in use as well as in clinical development. Resistance to aminoglycosides is predominantly due to enzymatic inactivation in the periplasmic space, the exact nature of the modification depending on the particular aminoglycoside. The major mechanism for tetra-cycline resistance involves an active efflux system, while sulfonamide resistance is due to an additional, plasmid-mediated, sulfonamide-resistant, dihydropteroate synthase target. Overall, the biggest clinical threat is multi-drug resistance, exacerbated by the absence of any new agent in development.
4:30 Bisphosphonated Rifamycin Prodrugs for the Treatment of Osteomyelitis
Dario Lehoux, Ph.D., Director, In Vivo-Pharmacology, Targanta Therapeutics
Osteomyelitis is an infection of bone primarily caused by staphylococci. Its treatment often requires a combination of surgical intervention and prolonged antibiotic therapy. Treatment is complicated by poor accessibility of both immune defenses and antibacterial agents to the focus of infection. A method by which agents could be de-livered to the site of infection is postulated to greatly improve efficacy and convenience relative to current treatments. Here we report the development and in vivo evaluation of a new class of prodrugs whereby rifamycins are tethered to a bisphosphonate functional group with high affinity for osseous tissues. The ability of the prodrugs to deliver their active moiety to the bone and to release it over time has been demonstrated, as has the efficacy of the prodrugs both in preventing and in treating bone infections in accepted animal models.
5:00 End of Conference