Sessions:

• Genomics-Lessons Learned

• Bioinformatics for Predicting Novel Targets

• Optimizing b-Lactamase Inhibition

• From Discovery to Delivery-Novel Insights

• Resistance is Futile

• Novel Targets

• Emerging Technologies and Drug Designs

SCIENTIFIC ADVISORS:
Scott D. Mills, Ph.D., Principal Scientist, Infection Discovery, AstraZeneca R&D
Michael J. Pucci, Ph.D. Achillion Pharmaceuticals
Lynn L. Silver, Ph.D., LL Silver Consulting, LLC

Wednesday, March 21

7:30 Pre-Conference Short Course Registration 

11:30 Main Conference Registration 

12:30 Chairperson’s Opening Remarks 
Lynn L. Silver, Ph.D., LL Silver Consulting, LLC

1:20 What Can Genomics Deliver? 
Scott D. Mills, Ph.D., Principal Scientist, Infection Discovery, AstraZeneca R&D 
In the last 10–15 years there has been a significant shift in the antibacterial drug discovery paradigm. At many pharmaceutical companies, there is less emphasis on whole-cell screening of natural products or synthesizing analogs within older antibacterial classes, and more focus on discovering first-in-class antibacterials derived from target-based screening. Genomics has been heralded as a means to accelerate this discovery process by identifying new targets that can be used in the relentless search to overcome resistance. But is it realistic to expect that exploitation of this technology will bring new drugs to market with a higher success rate, or even faster pace? Genomics is only one of several newer technologies applied to the discovery process, and cannot address some of the other key hurdles involving DMPK or safety issues. Nevertheless, genomics has delivered critical tools that support high-throughput target assessment and improved bioinformatics platforms. Significantly, genomics has facilitated the development of robust genome-scale genetic approaches, and valuable advances will continue to become available.

1:50 Prediction of Drug Targets in Salmonella Using a Hybrid Computational Approach 
Jason McDermott, M.D., Ph.D., Scientist III, Computational Sciences & Mathematics Division, Pacific Northwest National Lab (Battelle) 
We have predicted novel virulence factors secreted via the type III secretion system in Salmonella typhimurium using an approach which integrates machine learning techniques, knowledge-based screening and experimental data. Assessment of the machine-learning method shows that it performs very well to predict known secreted virulence factors. More importantly, preliminary experimental verification of these predictions has identified a novel virulence factor and its chaperone demonstrating the utility of our approach in identifying potential drug targets in Salmonella typhimurium. 

2:20 Grouping Antimicrobials Based on their Mechanism of Inhibition using Isobologram Arrays 
Lawrence Wiater, Ph.D., Senior Scientist, Research and Development, Biolog, Inc. 
Pairs of antimicrobials can interact additively, synergistically or antagonistically to prevent microbial growth, effects which are quantified by isobolograms that plot growth at different combinations of two inhibitors each at fractional minimal inhibitory concentrations. An array of synergy/antagonism values can be extracted from isobolograms made between one antimicrobial and a panel of diverse inhibitors. Upon clustering using Pearson distance with Ward linkage, structurally diverse antimicrobials were placed in groups whose members have the same reported mechanism of inhibition. Databases built on synergy/antagonism array values may be used to identify antimicrobials by their mechanism of inhibition in vivo within days, to identify antagonism and synergy with other antimicrobials and to exquisitely guide structure activity relationships. 

2:50 Refreshment Break, Poster and Exhibit Viewing

3:30 PK-PD in Antiinfective Development: Progressing Compounds to Clinical Trials and Beyond
Michael N. Dudley, Pharm.D., FIDSA, Vice President, Drug Development, Mpex Pharmaceuticals 

4:00 The Future of b-Lactamase Inhibition 
Robert Bonomo, M.D., Section Chief, Department of Infectious Diseases, Louis Stokes VAMC 
Since their initial discovery, b-lactamase inhibitors (clavulanate, sulbactam, and tazobactam) have been extremely important in our therapeutic arsenal. Paired with b-lactams, they have preserved the longevity of key antibiotics. Recently, novel findings using a variety of modalities are elucidating key insights into the mechanism of inhibition by these compounds. Work with novel mechanism based b-lactamase inactivators that differ from classical b-lactamase inhibitors and carbapenems is revealing key interactions. The future development of b-lactamase inhibitors also requires intimate knowledge of the novel b-lactamases that are emerging using a multidisciplinary approach. 

4:30 6-Methylidene Penems as Broad Spectrum b-Lactamase Inhibitors: SAR Studies in Combination with b-Lactam Antibiotics
Aranapakam M. Venkatesan, Ph.D., Chemical and Screening Sciences, Wyeth Research 
Inhibitors of bacterial b-lactamases in combination with other antibiotics have been used extensively in the clinical setting to overcome resistance due to b-lactamase production. Clinically used antibiotic/inhibitor combinations cover class-A producing pathogens, but have very little effect on class-C and ESBL producing organisms. However, methylidene penem inhibitors have shown promising broad-spectrum activity. In the present work, based on modeling studies, novel methylidene penems (3), having bicyclic and tricyclic heteroaryl moieties were designed and synthesized by a novel route. The structure activity relationship and mechanism of action of this class of compounds will be discussed.

5:00 Progress of a Novel Non-Beta-Lactam Beta-Lactamase Inhibitor towards the Clinic
Christine Miossec, Ph.D., Senior Research Scientist, Novexel 
NXL104 is a -lactamase inhibitor of a novel non -lactam class of compounds. NXL104 inhibits -lactamase enzymes through the formation of a stable covalent carbamoyl linkage. The spectrum of NXL104 covers both Ambler class A and class C enzymes and includes the ESBLs. The ability of NXL-104 to protect various -lactams from hydrolysis has been demonstrated both in vitro and in vivo with class A and class C producing Enterobacteriaceae. Pre-clinical drug safety studies have shown no findings that would preclude further development. Novexel’s near-term development plans are to test NXL104 in phase-I trials alone and in combination with an i.v. -lactam antibiotic.

5:30 "Best Poster" Presentation

5:40 Share and Gain Roundtable Discussions 
One hour focus groups designed to discuss important and challenging topics related to Antibacterial Drug Discovery. This is a moderated discussion with brainstorming and interactive problem solving between scientists from diverse areas who share a common interest in the discussion topic. These forums are for open discussion of scientific challenges, and not sales opportunities. We emphasize that this roundtable is for an interactive exchange among scientists and is not meant to be, in any way, a corporate or product discussion. 
Topics:

• Predictive Modeling and Testing-what works? 
• Structure Based Drug Design-current challenges? 
• Lead Optimization 
• Targets and Target Selection 
• Safety Considerations 

6:30 End of Day One