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Overcoming Resistance: New Strategies to
Develop Antibiotics and Antifungals
December 9 - 10, 1999
San Diego Marriott Hotel & Marina
San Diego, CA
iir-ny.com
Agenda:
Dec 9...
8:00
Conference Registration & Continental Breakfast
8:45
Co-Chairperson's Welcome and Opening
Remarks
Francis Tally, PhD, Executive Vice President,
Scientific Affairs, Cubist Pharmaceuticals
9:00
Keynote Address
State of the Industry Overview - Where We Are
and Where We're Going in Antimicrobial
Discovery
This presentation provides an overview of the
pharmaceutical industry's efforts to discover and
develop drugs ? both efforts to date and future
directions. In particular, the evolution of the process
of Discovery and inclusion of new tools such as
surveillance data, genomics, bioinformatics is
included. Approaches to potential intervention
including bactericidal/bacteriostatic, adjunct
therapy, and antimicrobial potentiation are included.
John F. Barrett, Executive Director Anti-Infectives
Drug Discovery, Bristol-Myers Squibb
John F. Barrett, PhD, is Executive Director of
Anti-Infectives Research at Bristol-Myers Squibb.
With 15 years experience in the pharmaceutical
industry, he has experience in a wide breathe of
antibacterial and antifungal discovery and
development efforts, at Pfizer and Johnson &
Johnson?s Pharm. Res. Inst., before joining BMS in
1997. He leads a group of research scientists
seeking the identification of novel antimicrobials and
antifungals through a combination of classical
discovery techniques and genomics.
10:00
Bactericidal/Permeability-Increasing Protein:
Enhancing the Activity of Current Antibiotics and
Reversing Antibiotic Resistance with rBPI21
rBPI21, a recombinant protein derived from the
N-terminal domain of human
Bactericidal/Permeability- Increasing protein (BPI),
possesses a number of anti-infective properties of
clinical interest, including direct antibacterial action,
high-affinity binding to lipopolysaccharides (LPS)
from gram-negative bacteria, and the ability to clear
and neutralize the inflammatory activities of bacteria
and their LPS. In addition, recent studies have
demonstrated that rBPI21 also enhances the activity
of numerous antibiotics both in vitroand in vivo, and
can overcome resistance to these antibiotics in
vitro. Current data also suggest that peptides
derived from rBPI21 have broad antibacterial and
antifungal activity. These data suggest that rBPI21,
or molecules derived from it, may have clinical utility
in extending the use of current antibiotics and
helping to control the emerging threat of antibiotic
resistance.
Stephen F. Carroll, PhD, Vice President, Preclinical
Research, XOMA (US) LLC.
10:45
Mid-Morning Refreshment Break
11:15
Metalloenzymes, A Family of Targets for the
Discovery of Novel Antimicrobials for
Combinatorial Libraries
This session describes a metalloprotein family of
genes essential for growth or that are involved in
antibiotic resistance. Combinatorial libraries based on
pharmacophores that bind to the metal ion at the
active site are synthesized and screening assays
devised. These libraries are screened using
enzyme-based screens and whole-cell GTS-based
screens. The active compounds are then evaluated
for their mechanism of action and antimicrobial
activity.
Specificity of the GTS assay
Determining the mode of action in whole cells
Utilizing combinatorial libraries to discover
novel antibiotics
Joaquim Trias, Assistant Director of Microbiology,
Versicor
12:00
Ziracin? and Resistant Gram Positive Infections:
Clinical Case Review of Experience with
Evernamicin (SCH 27899)
This presentation highlights a new antibiotic product
currently in development. Hear an update on the
following:
Review Background information on
everninomicins and Ziracin?
Summary of Completed Ziracin? Clinical
Studies
Review sample cases (VRE, glycopeptide
intolerant subjects).
Catherine J. Hardalo, PhD, Associate Clinical
Project Director Anti-Infectives Clinical Research
Group, Schering Plough Research Institute
12:45
Luncheon for Speakers & Delegates
2:00
VITA? ? Validation of In Vivo Targets and
Assays for Anti-Infectives
Cubist Pharmaceuticals has developed a technology
to validate targets in pathogens as well as animal
model infections. The technology, termed VITA?
differs significantly from traditional target validation
approaches provided by disruption of gene
expression. Initially, peptide binders are identified to
the target of interest. These peptides are expressed
intracellularly to examine pathogen growth rate and
infectivity. Alterations in growth rate and protection
in animal models of infection have been shown to be
the result of peptide binding to functionally relevant
sites on essential proteins. Finally, validated peptide/
protein combinations are configured in a binding
assay to detect small molecule inhibitors. An
essential component to the technology has been
identification of tightly controlled gene expression
systems for E. coli and S. aureus.
Using the technology, it has been demonstrated that
regulated intracellular expression of peptide inhibitors
to specific amino acyl-tRNA synthetases in E. coli
and S. aureus drastically inhibited bacterial growth in
vitroand protected against a lethal infection in vivo.
A homogeneous fluorescence polarization assay has
been established and used for the identification of
inhibitors with nanomolar to micromolar potency. This
technology is used to accelerate the identification
and screening of novel targets for drug discovery.
Francis Tally, PhD, Executive Vice President,
Scientific Affairs, Cubist Pharmaceuticals
2:45
Mid-Afternoon Refreshment Break
3:15
How Pneumococcal Strains Evade Macrolides:
The Impact on Drug Discovery
The mechanisms responsible for macrolide resistance
in Streptococcus pneumoniae mutants selected from
susceptible strains by serial passage in azithromycin
were investigated. In addition, macrolide-resistant
clinical pneumococcal isolates with interesting
macrolide-lincosamide-streptogramin B phenotypes
were evaluated. None of the strains had a resistance
determinant known to mediate erythromycin
resistance ( erm, mef, ereA, ereB, mphA, mphB,
mphC, msrA). Rather, the mechanisms were all
target-directed:
Changes of C2611A, C2611G, A2058G, or
A2059G ( Escherichia coli numbering) in 23S
rRNA
Mutations in the conserved region of ribosomal
protein L4 ( 63 KPWRQKGTGRAR 74 ).
Understanding the mechanisms of resistance to a
known drug class serve to guide new structural
forays into the class and, hopefully, allow us to stay
ahead of the pathogens.
Joyce Sutcliffe, Principal Research Investigator,
Pfizer, Inc.
4:15
Strategies for the Target-Based Discovery of
Antimicrobial Translation Inhibitors
This presenter describes several approaches being
used at RiboGene to systematically apply a
target-based drug discovery strategy to the
identification of new antibacterial and antifungal
translation (protein synthesis) inhibitors. The
presentation includes summary background
information on translation inhibitors and targets as
well as results obtained for several RiboGene
antibacterial and antifungal translation inhibitor
projects.
Charles Gluchowski, PhD, Senior Director of
Research, Ribogene, Inc.
5:00
Conclusion of Day One
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Dec 10...
8:00
Continental Breakfast
8:30
Co-Chairperson?s Recap of Day One & Opening
Remarks
George H. Miller, PhD, Sr. Vice President for
Research and Development, Microcide
Pharmaceuticals Inc.
8:45
Mining the MUR Pathway for Novel Antibiotics
We describe a method to assay simultaneously six
enzymes involved in cell wall (murein) biosynthesis
under conditions designed to discover inhibitors of
any one of the component enzymes with equal
sensitivity. Biosynthesis of murein is a unique and
essential process in bacteria, and as such, is an
attractive target for antibiotic development. While
the well-known á-lactam antibiotics inhibit the final
periplasmic steps of murein biosynthesis, the
cytoplasmic enzymes MurA-F, that catalyze the
early phase of cell wall construction, have not been
thoroughly interrogated for inhibitors, mainly because
their substrates are not easily made or isolated. This
presentation describes the development of high
throughput, cell free Mur pathway assay that is
enzymatically engineered to detect inhibitors of any
and all of the components with equal likelihood.
Since pathway intermediates are synthesized in situ,
isolated substrates for the downstream enzymes are
not required in the assay. Apart from the savings of
reagents and time that screening six enzymes
simultaneously affords, this assay provides the
opportunity to detect inhibitors of multiple enzymes
(multimodal inhibitors) that only could be found in
the context of an intact pathway.
David L. Pompliano, PhD, Executive Director,
Dupont Pharmaceuticals
9:30
Overcoming Resistance to Existing
Antimicrobials - Inhibitors of Efflux Pumps in
Pathogenic Bacteria and Fungi
Efflux pumps are a significant cause of resistance to
several classes of antibacterials - fluoroquinolones,
á-lactams, macrolides, tetracyclines and
chloramphenicol as well as to antifungals - azoles
and allylamines. Inhibition of the efflux of these
antiinfectives often results in a significant change in
the susceptibility of strains with either intrinsic or
acquired resistance. Studies with inhibitors of efflux
pumps can be used to define the role of efflux pumps
relative to non-efflux-mediated mechanisms of
resistance as well as defining their potential clinical
role.
George H. Miller, PhD, Sr. Vice President for
Research and Development, Microcide
Pharmaceuticals Inc.
10:15
Mid-Morning Refreshment Break (Also a
Convenient Time for Hotel Check-out)
10:45
Overcoming Macrolide Resistance: Breakpoints,
Pharmacokinetics, and New Ketolides
The prevalence of antimicrobial resistance in
bacterial species involved in community-acquired
respiratory tract infections is increasing, and thus,
the effectiveness of many commonly used
antibacterial agents is diminished. Macrolide
antibiotics have been a mainstay of therapy for
community-acquired respiratory tract infections.
Understanding the mechanisms of macrolide
resistance in key respiratory pathogens allows for
effective use of existing agents such as
clarithromycin and development of new agents such
as ABT-773 to provide empiric antibacterial coverage
in the outpatient environment.
Macrolide resistance In H. influenzae has not
been documented; the apparent low
susceptibility to clarithromycin in H. influenzae
may be a function of the test method and the
clinical breakpoint.
In streptococci, the most common mechanisms
of resistance to macrolides is rRNA methylation
(erm) or efflux (mef). Despite the increasing
prevalence of macrolide resistance in S.
pneumoniae, clinical failures with clarithromycin
treatment have not been increasing.
The novel ketolide antibiotic, ABT-773, has
demonstrated potent in vitro activity and in
vivo efficacy in animal models of respiratory
tract infection, including streptococci resistant
to classic macrolides via rRNA methylation or
efflux. ABT-773 possesses significant
advantages over the potency and antimicrobial
profile of marketed macrolide antibiotics,
suggesting it may be a therapeutically useful
new antibacterial agent for the treatment of
respiratory tract infections.
Angela M. Nilius, PhD, Group Leader, Discovery and
Clinical Microbiology, Abbott Laboratories
11:45
Daptomycin: A New Lipopetide Antibiotic for
Gram-positive Infections
The alarming increase in the incidence of
gram-positive infections has prompted renewed
interest in the development of new classes of
antibiotics. One such agent is daptomycin, a novel
lipopeptide with bactericidal activity in vitroagainst
most clinically relevant gram-positive bacteria,
including resistant pathogens. Daptomycin exhibited
a favorable safety profile in nonclinical studies and in
clinical trials conducted in the 1980s and early 1990s
by the previous manufacturer, Eli Lilly. Cubist
Pharmaceuticals, Inc. has resumed the clinical
development of daptomycin, with an IND filed at the
end of 1998, and an NDA planned for 2001. Ongoing
clinical investigations include a blinded, comparative,
Phase III study of intravenous daptomycin at a dose
of 4 mg/kg once a day for the treatment of
complicated skin and soft tissue infections, and an
open label Phase II study evaluating three dose
regimens of daptomycin in the treatment of
bacteremia. Interim results from the bacteremia trial
are presented here.
Francis Tally, PhD, Executive Vice President,
Scientific Affairs, Cubist Pharmaceuticals
12:30
Conference Concludes
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