Antibacterial Research and Development



Antibacterial Research and Development


According to the Centers for Disease Control and Prevention, antibiotic-resistant infections are associated with an additional 23,000 deaths and 2 million illnesses in the United States each year. The estimated annual impact of antibiotic-resistant infections on the national economy is $20 billion in excess direct health care costs, and as much as $35 billion in lost productivity from hospitalizations and sick days. By holding the Re-Entering Antibacterial Drug Development Summit, we at Cambridge Healthtech Institute are trying to contribute to the efforts to revive antibacterial pipeline, and to improve antimicrobial stewardship in the United States and worldwide. This Summit is designed as a forum for knowledge and opinion exchange between the major stakeholders, who are shaping the current state of antibacterial discovery and development.


Monday, November 16

7:15 am Registration and Morning Coffee

8:15 Welcome Remarks from Conference Producer

KEYNOTE SESSION

8:20 Chairperson’s Opening Remarks

Antonio DiGiandomenica, Ph.D., Scientist II, Infectious Diseases, MedImmune

8:30 Novel Monoclonal Antibodies for the Prevention and Treatment of Bacterial Infections

Steven ProjanSteven J. Projan, Ph.D., Senior Vice President, R&D, Innovative Medicines Unit; Head, Infectious Diseases & Vaccines, MedImmune

The second decade of the twenty-first century marks a perfect storm of patent expirations, contracting western economies, and increasing demands from “payers” that pharmaceuticals demonstrate cost effectiveness of their drugs. The result is the shrinking of “big pharma” right before our eyes and nowhere has the impact been felt more than in infectious disease research at large pharmaceutical companies. All the while, bacterial resistance to antibiotics is increasing even as the number of new drugs being developed to treat bacterial infections is at its lowest point since the drawn of the antibiotic era. This surfeit of new agents implies that the “traditional” approaches to drug discovery and development have run their course and novel (entrepreneurial, opportunistic) approaches for the treatment and prevention of microbial infections (and forestalling the emergence of resistance) are required. Against that background we are have seen an increasingly convoluted regulatory regime with indications being parsed finer and finer yet with larger numbers of patients required to reach arbitrary (but often clinically meaningless) statistical endpoints. To date, there has been some modest biologics drug discovery efforts to discover novel antibacterial agents for the prevention and/or treatment of Staphylococcal, Pseudomonal and Clostridium difficile infections but these efforts now appear to be picking up speed and are progressing in the clinic. Is there hope?

9:00 Antibiotic Adjuvants to Reclaim Legacy Drugs

Gerard WrightGerard D. Wright, Ph.D., Director, Michael DeGroote Institute for Infectious Disease Research; Canada Research Chair in Molecular Studies of Antibiotics, Department of Biochemistry and Biomedical Sciences, McMaster University

Addressing the antibiotic crisis requires innovation in antibiotic discovery and exploration of orthogonal strategies that can widen our traditional thinking of antimicrobial therapy. One such approach is the systematic search for compounds that enhance the activity of existing antibiotics in resistant bacteria. This can include compounds that block resistance enzymes, perturb efflux, or otherwise potentiate antibiotic action. Our screens of resistant bacteria suggest that microbial natural products are a rich source of such antibiotic adjuvants that work by a number of mechanisms. Our efforts and recent research in this area will be highlighted.

9:30 Trench Warfare: The Battle to Push Back the Lines of Gram-Negative Resistance

Todd BlackTodd A. Black, Ph.D., Executive Director, Infectious Diseases, Merck

Antibiotic resistant Gram-negative bacteria are increasing in prevalence. Some strains are now resistant to all classes of antibiotics, including polymyxins. The discovery of new classes of agents that are effective against Gram-negative pathogens has thus far proven to be an insurmountable challenge despite years of intensive efforts. The recent development of compounds that address specific subsets of resistance mechanisms have thus far been the only effective response. However, this approach provides only incremental improvements in strain coverage and presents challenges identifying the right patients and strategies to ensure appropriate use to reduce rapid development of resistance.

Polyphor10:00 A Novel Class of Antibiotics against MDR Gram-Negative ESKAPE Pathogens

Daniel Obrecht, Ph.D., CSO, Polyphor

A novel class of antibiotics with high potency against MDR Gram-negative ESKAPE pathogens was discovered applying the Protein Epitope Mimetic (PEM) technology. The frontrunner POL7080 is a Pseudomonas-selective antibiotic with a novel MoA [2], is currently in Phase II clinical trials and was partnered with Roche in November 2013. Based on the unique MoA of POL7080, novel PEM antibiotics were designed and synthesized with potent activity against other Gram-negative ESKAPE pathogens, including MDR clinical isolates.

10:30 Coffee Break with Exhibit and Poster Viewing

MEDICINAL CHEMISTRY APPROACHES

11:00 Bringing the Full Power of Chemical Synthesis to Bear on the Discovery of New Antibiotics

Andrew MyersAndrew G. Myers, Ph.D., Amory Houghton Professor of Chemistry, Department of Chemistry & Chemical Biology, Harvard University

Many of the classes of antibiotics in current use were revealed by screening of fermentation broths in the era circa 1940–1960, considered to be a golden age in the discovery of antibiotics. Since then new antibiotics have been developed mainly by the process of semi-synthesis, where natural (fermentation) products are modified by chemical synthesis. Many important therapeutic agents have arisen by semi-synthesis and no doubt many more remain to be discovered in this way, but the process is inherently limited. This lecture will focus on the development of new platforms for the discovery of antibiotics by applying the power of convergent chemical synthesis, providing readily modifiable scaffolds that were previously inaccessible by any other means.

11:30 Gram-Negative Antibiotics: The Importance of Compound Properties for Drug Discovery

Heinz MoserHeinz E. Moser, Ph.D., Executive Director, Chemistry Infectious Diseases, Global Discovery Chemistry, Novartis Institutes for BioMedical Research

While the biochemical screening of essential targets has often produced hits, the conversion of such hits to antibiotics with target-driven activity on Gram-negative bacteria has proven to be difficult. A thorough analysis of the property space from existing antibiotics has shed some light on particular compound requirements for successful therapeutics that are largely driven by the unique architecture of the bacterial cell wall. This topic and application of this insight in existing antibacterial projects will be discussed.

12:00 pm Sponsored Presentation (Opportunity Available)

12:30 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own

1:15 Session Break

NON-TRADITIONAL APPROACHES

2:00 Chairperson’s Remarks

Heinz E. Moser, Ph.D., Executive Director, Chemistry Infectious Diseases, Global Discovery Chemistry, Novartis Institutes for BioMedical Research

2:10 New Antibiotics from Natural Products

Kim LewisKim Lewis, Ph.D., University Distinguished Professor, Director, Antimicrobial Discovery Center, Department of Biology, Northeastern University

Resistance development and inability to effectively eradicate an infection are the deficiencies of currently available antibiotics. Reexamining old compounds led us to focus on acyldepsipeptide, which kills both growing and dormant persister cells by activating the ClpP protease. Screening uncultured bacteria produced several novel antimicrobials. Lassomycin kills dormant cells of M. tuberculosis by activating ClpC1, resulting in ATP depletion. Teixobactin is a novel cell wall synthesis inhibitor which binds to precursors of peptidoglycan and wall teichoic acid. There is no detectable resistance development to teixobactin. Pulse-dosing with teixobactin eradicates planktonic and biofilm cultures.

2:40 Re-Entering the Antibacterial Space for the Microbiota Opportunity—Worth the Investment and Effort?

David MartinDavid W. Martin, M.D., CEO, AvidBiotics

The gut and other human microbiota are unquestionably important for health, healthcare and disease care. Currently available antibacterial agents cannot be used to safely manipulate microbiota, leaving the addition of microbes via low margin probiotics or perhaps prebiotics as the only approach. An alternative is to re-enter the antibacterial space by discovering and developing precision antibacterial agents that can subtract suspected or validated causal microbes, secure beneficial claims, and market high value antibacterial products—precision drugs for bad bugs, PD4BB.

Lakewood Amedex3:10 A New Class of Antimicrobials for Antibiotic-Resistant and Difficult to Treat Infections

Paul DiTullio, Vice President, Product Development,
Lakewood-Amedex, Inc.

Antibiotic-resistant bacteria pose an increasing threat to the US Healthcare system that has been highlighted by an almost empty pipeline of new antimicrobials. Lakewood-Amedex is developing a new class of antimicrobials, termed bisphosphocins®, that have the potential to change the way bacterial infections are treated.

3:40 Refreshment Break with Exhibit and Poster Viewing

4:10 PANEL DISCUSSION:
Discovery and Development of Broad Spectrum and Pathogen-Specific Antibacterials: Where Are the New Treatments Coming From?

Moderator: Gerard D. Wright, Ph.D., McMaster University
• Where are the new small molecule agents coming from? What should we be doing differently?
• Can we and should we move beyond traditional antibiotics? Broad spectrum and/or narrow spectrum?
• How do we develop non-traditional antibiotics and work with regulatory authorities to obtain a path to approval? e.g – persister inhibitors, microbiome modifiers, etc.
• Are there good opportunities for combining synergists with older agents to renew their utility?
• How do we continue to fund early stage antibacterial drug discovery and development?
 

Panelists: Speakers of the Day

EMERGING COMPANIES, TECHNOLOGIES AND COMPOUNDS

4:50 Chairperson’s Remarks

Christopher-Paul Milne, Ph.D., Director, Research, Tufts CSDD, Tufts University School of Medicine

5:00 What Does the Company Landscape Look Like for Anti-Bacterials and How Will It Change by 2020?

Christopher-Paul MilneChristopher-Paul Milne, Ph.D., Director, Research, Tufts CSDD, Tufts University School of Medicine

After following the development of the contours of the medical countermeasures (MCMs) landscape for almost 15 years, certain prominent features are beginning to emerge: what works and what doesn’t in terms of incentives; the demographics of the companies that have stayed in the game; the competition dynamic from other therapeutic areas; and, gaps likely to be filled or unfilled in the next five years. These features will be discussed in the overall context of the limited policy awareness of the length of the timeline disconnect between even optimal pipeline output and the onset of widely felt public health impacts.

5:30 A Native Human Monoclonal Antibody that Disrupts Established Biofilms

Lawrence Kauvar, Ph.D., CSO, Trellis Bioscience, LLC
A family of DNA binding proteins (IHF/HU/DNABII) anchor extracellular DNA and form a key structural element of biofilms. TRL1068 is a monoclonal antibody cloned from human B-cells that binds IHF homologs from diverse bacterial species with high affinity. Affinity extraction of the protein leads to biofilm breakdown and resensitization to antibiotics both in vitro and in animal models.
 
 

5:45 Novel Therapies for Urgent Threats: A Pipeline of First-in-Class Antibiotics for the Treatment of Life Threatening Infections

Thale JarvisThale C. Jarvis, Ph.D., CSO, Crestone, Inc. 
CRS3123 is in clinical development for treatment of Clostridium difficile infection, a devastating gastrointestinal infection. Key differentiating features include 1) narrow spectrum activity which protects normal gut flora, 2) inhibition of sporulation, and 3) inhibition of toxin secretion. These features promote rapid efficacy and reduced recurrence. Crestone’s preclinical pipeline includes novel polymerase inhibitors for treatment of MRSA, VRE and anthrax.

 

 

6:00 Gyramides: Potent, Synthetic Broad-Spectrum Antibiotics that Inhibit DNA Gyrase through a New Mechanism

Douglas WeibelDouglas B. Weibel, Ph.D., Associate Professor of Biochemistry, Chemistry, and Biomedical Engineering, University of Wisconsin, Madison 
We have discovered, characterized, and are developing a new class of allosteric ATPase inhibitors of DNA gyrase. These compounds are broad spectrum bacteriostatic antibiotics with a minimum inhibitory concentration of ~1 ug/mL against many pathogenic bacteria. The compounds have a mechanism that differentiates them from novobiocin and ciprofloxacin, including their region of binding. Importantly, the gyramides display very little cross resistance with ciprofloxacin and novobiocin, enabling these antibiotics to kill cipro- and novobiocin-resistant bacteria.


 

6:15 Sequence-Specific Antimicrobials: Better Weapon against Multi-Resistant Bacteria?

Xavier DuportetXavier Duportet, Ph.D., CEO, Eligo Bioscience
Eligo Bioscience developed the first sequence-specific antimicrobials: the eligobiotics. Eligobiotics can be programmed to selectively eradicate bateria based on their genome. We have demonstrated the effectiveness of eligobiotics in vitro and in vivo by killing MRSA and Enterohemoragic E.coli (published in 2 Nature Biotech papers). We are a spin-off of MIT and Rockefeller. We are now developing eligobiotics to decolonize the gut of patients from virulent and resistant bacteria while leaving the rest of the flora intact. Eligobiotics rely on the delivery of a programmable CRISPR/Cas synthetic circuit into bacteria via engineered phagemids.
 

6:30 Welcome Reception with Exhibit and Poster Viewing

7:30 Close of Day

Tuesday, November 17

7:30 am Breakout Discussions with Continental Breakfast (see web for details)

CASE STUDIES

8:30 Chairperson’s Remarks

Kit PoglianoKit Pogliano, Ph.D., Professor, Division of Biological Sciences, University of California, San Diego

 

8:35 Disrupting Pseudomonas Biofilms? There’s a mAb for That.

Antonio DiGiandomenicaAntonio DiGiandomenica, Ph.D., Scientist II, Infectious Diseases, MedImmune

Bacterial biofilm formation on medical devices is a common cause of serious persistent and recurrent infections and a significant driver of increased healthcare costs. The opportunistic pathogen Pseudomonas aeruginosa is a notorious biofilm producer, causing life-threatening infections in critically ill patients. Given the antibiotic recalcitrance of biofilm communities, novel therapeutic solutions are needed. In this presentation, I will discuss promising mAb-based activities and contributing mechanisms of action to prevent and treat P. aeruginosa biofilms.

9:05 Teaching Old Antibiotics New Tricks: A Combination Approach to Anti-Infective Therapy

Troy ListerTroy Lister, Ph.D., Head, Chemistry, Spero Therapeutics

Gram-positive and Gram-negative bacteria possess many conserved common biological functions, which are essential for growth and survival. These represent attractive targets for antimicrobial research. For Gram-negative organisms, translating potent cell-free target-based inhibitors to potent cellular inhibitors is especially difficult due in large part to a highly impenetrable outer membrane. Spero Therapeutics is developing a series of NMEs that specifically interact with the outer membrane of Gram-negative bacteria. These molecules compromise the integrity of this barrier and drastically increase the rate at which antimicrobial compounds penetrate the organism. We have identified multiple combination products with potent activity against Gram-negative organisms, including MDR strains.

9:35 Sponsored Presentation (Opportunity Available)

10:05 Coffee Break with Exhibit and Poster Viewing

FROM MECHANISM OF RESISTANCE TO MECHANISM OF ACTION

10:35 Understanding Drug Resistance of Gram-Negatives: Contributions of Basic Science to Drug Discovery Efforts

Herbert SchweizerHerbert P. Schweizer, Ph.D., Preeminence Professor of Microbiology, Department of Molecular Genetics and Microbiology, College of Medicine, Emerging Pathogens Institute, Institute for Therapeutic Innovation, University of Florida

Drug resistance is an ancient phenomenon that predates the modern antibiotic era. Now, emergence of bacterial resistance has outpaced the speed by which new antibiotics are being developed. Government entities in the United States and Europe recently declared antimicrobial resistance a public health crisis. The resistance problem is especially acute with Gram-negative bacteria. This presentation will discuss how basic science efforts aimed at understanding various aspects of drug resistance in Gram-negative bacteria can make significant contributions to drug discovery efforts.

11:05 Context-Specific Action of Antibiotics Targeting the Ribosomal Peptidyl Transferase Center

Alexander MankinAlexander Mankin, Ph.D., Professor, Center for Pharmaceutical Biotechnology, Department of Medicinal Chemistry & Pharmacognosy, University of Illinois, Chicago

Many old (e.g. chloramphenicol) and new (e.g. linezolid) antibacterials inhibit bacterial growth by targeting the ribosomal Peptidyl Transferase Center (PTC). They are thought to inhibit formation of any peptide bond. In reality, however, chloramphenicol and linezolid actively interfere with formation of peptide bonds between certain combination of the donor and acceptor substrates, but fail to do so with the other substrates. Understanding that these inhibitors exhibit context-specific action illuminates the ways for their improvement and unraveling the resistance mechanisms.

11:35 Bacterial Cytological Profiling, a Tool for Antibacterial Drug Discovery and Susceptibility Testing

Kit PoglianoKit Pogliano, Ph.D., Professor, Division of Biological Sciences, University of California, San Diego

Bacterial cytological profiling (BCP) provides a rapid and precise way to identify the mechanism of action for new antibacterial molecules, discriminating between drugs that target different steps in a pathway and identifying molecules that inhibit new drug targets. BCP provides insight into the role natural products play in shaping microbial communities. It also allows activity-guided purification of natural products and provides a rapid and highly accurate antibiotic susceptibility test.

12:05 Close of Conference


Track 1 | Track 2 | Track 3 




For more details on the conference, please contact:
Marina Filshtinsky, M.D.
Senior Director, Conferences
Cambridge Healthtech Institute
Phone: 781-972-5496
Email: mfilshtinsky@healthtech.com  


For exhibit & sponsorship information, please contact:
Carolyn Benton
Business Development Manager
Cambridge Healthtech Institute
Phone: 781-972-5412, Fax: (781) 972-5470
email: cbenton@healthtech.com  



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