New discovery platforms, novel screens and approaches are vital for development of new antibacterials and for ceasing the dangerous trends of multidrug microbial resistance. Clostridium Difficile, Carbapenem-Resistant Enterobacteriaceae and Neisseria gonorrhoeae, are the urgent threats according to CDC, and each provides specific scientific challenges for researchers. The third annual Antibacterial Discovery conference will be focusing on platforms, targets and preclinical approaches for new antibacterial agent discovery and development.

Final Agenda

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Wednesday, December 7

7:15 am Registration Open and Morning Coffee

ADDRESSING MULTIDRUG RESISTANCE

 7:50 Chairperson’s Opening Remarks

Lynn Silver, Ph.D., Silver Consulting, LLC

8:00 Improving Our Understanding of Porin Permeability in Gram-Negative Bacteria

Ruben Tommasi, Ph.D., CSO, Entasis

Studies on the permeation of carbapenems, including analogs which explore polarity differences, as well as the placement of charge are explored. Results which we have obtained so far suggest that not only is proper polarity important, but also the proper placement of charge about the molecule. Ultimately, our goal is to establish structure permeation relationships that could be used to proactively design molecules with superior permeation into Gram-negative pathogens across multiple chemotypes.

 8:30 Assessing Compound Permeability in Gram-Negative Bacteria to Enable Rational Drug Design

Thomas Krucker, Ph.D., Group Leader, New Technologies, Infectious Diseases Novartis Institutes for BioMedical Research

Accessing drug targets in the cytoplasm of Gram-negative pathogens is difficult because of the permeability barrier that limits the accumulation of promising antibiotics to effective levels within the cell. The ability to measure compound permeation and accumulation in Gram-negative bacteria is potentially an enabling component of structure-activity-relationships which guide rational drug design and optimization. Strategies addressing these challenges and the development of enabling technologies will be discussed.

9:00 Filling in the Gaps in the MDR Gram-Negative Pipeline

Todd A. Black, Ph.D., Executive Director, Infectious Diseases, Basic Research, Merck Research Laboratories

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 have 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.

 9:30 Novel Macrolides for Serious Infections

Richard Alm, Ph.D., Vice President Biology, Macrolide Pharmaceuticals

Macrolide antibiotics are among the safest and most effective classes of antibacterials, but the use of the class has been limited by increasing resistance in Gram-positive bacteria and longstanding resistance in Gram-negative bacteria. A complete synthesis developed by Prof. Andrew Myers at Harvard University allows for the first time the synthesis of a wide range of macrolides and insight into structure/activity relationships. Macrolide Pharmaceuticals has synthesized more than 600 novel macrolides, with excellent Gram-positive activity and encouraging activity against multi-drug resistant Gram-negatives.

10:00 Antibiotic Collaborative Drug Discovery Secure Data Sharing

Barry Bunin, Ph.D., CEO, Collaborative Drug Discovery, Inc.

With the resurgence of interest in the Antibiotic Drug Discovery field, it is critical that we learn from the past. To attack resistance smarter, we need new technologies, new modes of collaboration, and new ways to leverage historical data. Conceptually, by collaborating together, we mimic (with ideas and data) the processes bacteria use to transfer genomic and mechanistic information. Emerging models hold lessons for future industry and academic collaborations.

10:30 Coffee Break in the Exhibit Hall with Poster Viewing

11:00 Host-Directed Therapeutics to Regulate Bacterial Infection and Overcome Antimicrobial Resistance

Rekha G. Panchal, Ph.D., Branch Chief, Molecular and Translational Sciences Division, US Army Medical Research Institute of Infectious Diseases

Antimicrobial resistance is one of the greatest threats to human health worldwide. Despite the general recognition of the important role of the host’s defenses, most studies of antibiotic resistance focus on the interaction between the pathogen and the antibiotics and neglect the contribution of the host response. The host response to the pathogen is critical in the control of the emergence of antimicrobial resistance and the effective clearance of the pathogen. This presentation will focus on development of host-directed therapeutics as an adjunct treatment option for select Gram negative bacteria.

11:30 Antibacterial Discovery and Development in Veterinary Medicine

Jeff Watts, Ph.D., Research Director, External Innovation, Zoetis, Inc

Veterinary medicine is confronted with distinct antimicrobial resistance issues that include both foodborne and target animal pathogens. The discovery and development of novel antibacterials for use in treating animal diseases has unique challenges distinct from those in human health. For example, veterinary medicine will need novel, non-shared antibacterials that are effective in treating disease while addressing the unique cost limits and human food safety necessary for approval of a new agent.

12:00 pm Enjoy Lunch on Your Own

MEDCHEM APPROACHES

1:05 Chairperson’s Remarks

Patricia A. Bradford, Ph.D., Antimicrobial Development Specialists, LLC

1:10 Inhibitors That Target Serine and Metallo-Beta-Lactamases: Challenges and Opportunities

Olga Lomovskaya, Ph.D., Vice President, Biology, The Medicines Company

Earlier work in cyclic boronic acid beta-lactamase inhibitors (BLIs) identified vaborbactam, a potent inhibitor of the KPC (serine, Class A) carbapenemase that is now in clinical trials in combination with meropenem. More recent efforts that combined molecular modelling with traditional medicinal chemistry led to the discovery of a new series of potent cyclic boronic acid BLIs capable of inhibiting both serine and metallo carbapenemases.

1:40 Novel Inhibitors of Dihydrofolate Reductase – The Quest for G- Activity

Aileen Rubio, Ph.D., Head of Biology, Spero Therapeutics

Spero Therapeutics is working on novel inhibitors of dihydrofolate reductase (DHFR), a well-validated antibacterial target. The first-in-class DHFR inhibitor, trimethoprim (TMP), has had a long history of safe and effective use for the treatment of urinary tract infections, but its use has been eroded by the emergence of resistance. Our approach utilizes novel chemical matter, propargyl-linked antifolates, in a structure enabled drug discovery project to identify compounds with expanded spectrum to include MDR G- and TMP resistant organisms

2:10 Chemical Property Space – Considerations for Antibacterial Drug Discovery

Folkert Reck, Ph.D., Senior Investigator, Global Discovery Chemistry, Novartis Institutes for BioMedical Research

A discussion of impact of chemical property space on the challenges for Antibacterial Drug Discovery, namely safety, permeability into Gram-negative bacteria, and the quality of hits from screening.

2:40 Redesign of Biotin Carboxylase Inhibitors to Enhance Gram-Negative Membrane Penetration

Frederick Cohen, Ph.D., Director of Chemistry, Medicinal Chemistry, Achaogen

We present a case study in prospectively designing small-molecule inhibitors for penetration to the cytoplasm of Gram-negative bacteria. Careful optimization of molecular properties has allowed >100 fold improvement in antibacterial potency, while maintaining target binding potency. We also present data on the biology of AccC in Pseudomonas aeruginosa, including essentiality and mutation frequency.

3:10 Update on β-Lactam/β-Lactamase Inhibitors

Patricia A. Bradford, Ph.D., Antimicrobial Development Specialists, LLC

β-lactam/β-lactamase inhibitor combinations have been a mainstay of the antimicrobial armamentarium for many years. However, new β-lactamase in Gram-negative pathogens have diminished their usefulness. This presentation will discuss several new β-lactamase inhibitor combinations have been approved in recent years and others are in the development pipeline.

3:30 Bisphosphocins® – Antimicrobials for Broad Spectrum Indications Including Antibiotic-Resistant Bacterial, and Yeast, Fungal and Protozoan, Infections

Steve Parkinson, President & CEO, Lakewood-Amedex Inc.

Antibiotic-resistant bacterial infections caused by so-called ‘superbugs’ have continued to make successive headlines for the past few years, but never more so than this year when colistin-resitant E.coli was isolated from a Pennsylvanian woman. The medical community is screaming for new antibiotics, but for the most part, new derivatives of old classes are all that is in the pipeline – a short-term solution, not a long-term fix. However, Lakewood-Amedex has developed a truly new class of broad-spectrum antimicrobials, called bisphosphocins®, that have the potential to change the way bacterial infections are treated. Bisphosphocins® function through a novel mechanism of action involving membrane depolarization that leads to rapid bacterial cell death in less than one cell division time while harmless to the patient. This directly bactericidal mechanism is in stark contrast to the largely inhibitory action of most antibiotic classes and accounts for their activity against some of the most difficult to treat bacteria such as Borrelia borgdorferi, MDR-TB, and biofilm encased bacteria. Lakewood-Amedex has now advanced the first of these, Nu-3, into a Phase 1/2a human clinical trial for the treatment of chronically infected diabetic foot ulcers. In addition, bisphosphocins® have now shown activity against certain yeasts, fungi and protozoa.

3:45 Refreshment Break in the Exhibit Hall with Poster Viewing

METAGENOMICS AND GENOME MINING

4:10 Chairperson’s Remarks

Joyce Sutcliffe, Ph.D., Former Senior Vice President, Biology, Tetraphase Pharmaceuticals, Inc.

4:15 Antibiotics from Metagenomes

Sean F. Brady, Ph.D., Head, Laboratory of Genetically Encoded Small Molecules, The Rockefeller University

Uncultivated microorganisms are a very attractive source of potentially new natural products. Although there appears to be no easy way to culture this collection of unstudied microorganisms, it is possible to isolate large fragments of microbial DNA directly from environmental samples and clone this DNA into model bacterial systems in the lab. We are using both functional and sequence-based screening strategies to access new natural products from large environmental DNA libraries.

4:45 Genome Mining the Full Diversity of the Actinomycete Universe for Novel Antibiotic Discovery

Laurence E. Reid, Ph.D., CEO, Warp Drive Bio

Genome mining for novel natural products is an emerging approach to drive the discovery of new antibiotics. Actinomycetes have been the source of over two-thirds of clinically useful antibiotics of natural origin. However, the capability of actinomycetes to synthesize novel antibiotics has barely been tapped. Warp Drive Bio has sequenced over 135,000 actinomycete genomes to generate a proprietary database containing ~3.5 million biosynthetic gene clusters. Importantly ~75% of cluster families identified in our database have yet to be reported in the literature. Warp Drive is identifying biosynthetic clusters that produce new members of known antibiotic families (e.g. beta-lactams) as well as truly novel (“neomorph”) antibiotics

5:15 PANEL DISCUSSION: Host vs. Microbe Approaches

Moderator:
Joyce Sutcliffe, Ph.D., Former Senior Vice President, Biology, Tetraphase Pharmaceuticals, Inc.

Panelists: Speakers of the Day

• How can resistance erosion be part of the design of small molecules or host-pathogen approaches?

• Contrasts between pathogen-specific, host-microbe and small-molecule approaches

• How can guidance in the clinical microbiology lab be provided for host-specific or combinations of small-molecule and host-specific approaches?

5:45 Welcome Reception in the Exhibit Hall with Poster Viewing

6:45 Dinner Short Course: SC1: From “White Powder” to Drug: The Path from Antibacterial Discovery to the Clinic*

* Separate Registration Required

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Thursday, December 8

7:15 am Interactive Breakout Discussion Groups with Continental Breakfast

This session features various discussion groups that are led by a moderator/s who ensures focused conversations around the key issues listed. Attendees choose to join a specific group and the small, informal setting facilitates sharing of ideas and active networking. Continental breakfast is available for all participants. Details on the topics and moderators are available on the conference website.

Compound Permeability in Gram Negative Bacteria

Folkert Reck, Ph.D., Senior Investigator, Global Discovery Chemistry, Novartis Institutes for BioMedical Research

• Property space for permeability through porins and lipid bilayers
• Self-promoted uptake/ membrane disruption – Opportunities and Challenges (safety)
• Trojan Horse approach – Opportunities and Challenges (resistance, safety?)
• Property space for minimizing impact by efflux – any new insights?

Adjunct Antibacterial Therapeutics

Rekha G. Panchal, Ph.D., Branch Chief, Molecular and Translational Sciences Division, US Army Medical Research Institute of Infectious Diseases

• Current status on Adjunct therapeutics targeting the host, virulence factors or other resistance mechanisms
• Advances in screening technologies to identify adjunct therapeutics
• Product Development path for regulatory approval of adjunct therapeutics

β-Lactam/β-Lactamase Inhibitors

Patricia A. Bradford, Ph.D., Antimicrobial Development Specialists, LLC

• β -Lactamase Inhibitor Combinations (e.g. piperacillin-tazobactam, ceftolozane-tazobactam and ceftazidime-avibactam)
• Gram-negative pathogens
• Future Directions

Antibacterial Biologics

Eszter Nagy, M.D., Ph.D., Co-Founder and CSO, Arsanis, Inc; Managing Director, Arsanis Biosciences GmbH

• Which type of biologics (monoclonal antibodies, phages, antimicrobial peptides) have the best chance to break the disillusionment (due to past failures) and disbelief in antibacterial biologics?
• What is the most attractive clinical target: prophylaxis, preemptive therapy of high-risk individuals, or combination with / potentiation of existing antibiotic therapies?
• What are the major hurdles for pathogen-specific approaches (regulatory, commercial, etc)?

ANTIBACTERIAL BIOLOGICS

7:55 Chairperson’s Remarks

Eszter Nagy, M.D., Ph.D., Co-Founder and CSO, Arsanis, Inc; Managing Director, Arsanis Biosciences GmbH

8:00 A New Paradigm in the Infectious Disease Field: Preemptive Therapy of Severe Infections with Highly Potent Monoclonal Antibodies

Eszter Nagy, M.D., Ph.D., Co-Founder and CSO, Arsanis, Inc; Managing Director, Arsanis Biosciences GmbH

Severe bacterial infections are associated with high healthcare costs and mortality even with appropriate antibiotic therapy; the emerging antibiotic resistance further exacerbates this problem. Antibodies, induced by active immunization are proven to be the effector molecules in preventing bacterial infections. Even more powerful “designer” antibodies can be generated recombinantly and used in a preemptive approach for patients with high risk to develop severe infections, such as pneumonia and bacteremia.

8:25 Antibody-Antibiotic Conjugate for Treatment of Bacterial Infections

Wouter Hazenbos, Ph.D., Scientist, Infectious Diseases, Genentech

The Antibody-Antibiotic Conjugate (AAC) created at Genentech combines key properties of both antibody and antibiotic to treat bacterial infections. Features of the AAC for treatment of severe Staphylococcus aureus infections and the potential of AAC as a therapeutic platform will be discussed.

8:50 Target Discoveries for Immunotherapy against Antibiotics-Resistant Klebsiella Pneumoniae

Xiaodong Xiao, Ph.D., Senior Scientist, MedImmune

Immunotherapy represents a promising strategy against antibiotics-resistant Klebsiella pneumoniae. Critical to this strategy are the identifications of appropriate molecules that can serve as either vaccine antigen or antibody targets. Using a target-agnostic approach, we isolated a group of antibodies that displayed anti-Klebsiella pneumoniae activities. We went on to identify their common target as MrkA, a major type III fimbrial complex protein. The significance of the molecule and the method will be discussed.

9:10 Bezlotoxumab: A Biologics-Based Approach to Prevent Recurrent CDI

Alex Therien, Ph.D., Director, Biology-Discovery, Infectious Diseases, Merck

A novel approach to the prevention of recurrent CDI is the use of monoclonal antibodies(mAbs) directed against the toxins produced by C. difficile in patients receiving antibiotic therapy for CDI. Bezlotoxumab is a fully human mAb of that binds and neutralizes toxin B activity. Clinical trials have validated this approach as a means to reduce the recurrence of CDI.

9:35 Therapeutic Effects of a Topical Minocycline in an Inflammatory Skin Disorder Animal Model

Usha, Nagavarapu, Ph.D., Senior Director, Preclinical Drug Development, BioPharmX

Minocycline has been shown to be effective against P. acnes, a bacterium present on human skin, and associated with inflammatory acne. Oral minocycline is used to treat this disease, with undesirable systemic effects. Evaluation of a topical minocycline gel in an animal acne model to examine direct delivery of minocycline to acne lesions and potentially diminish the incidence of inflammation is presented.

10:05 Coffee Break in the Exhibit Hall with Poster Viewing

10:30 Chairperson’s Remarks

Menachem Shoham, Ph.D., Associate Professor, Biochemistry, Case Western Reserve University

10:35 Quorum-Sensing Inhibitors as Antibacterial Agents

Menachem Shoham, Ph.D., Associate Professor, Biochemistry, Case Western Reserve University

Quorum-sensing inhibitors curtail the ability of the pathogen to produce disease-causing toxins and virulence factors without killing the pathogen. No emergence of resistance has been reported so far. Interestingly, these agents also sensitize pathogens to antibiotics and inhibit biofilm formation.

11:05 Busting Silos: Host-Microbe Interactions in Infectious and Chronic Diseases

James R. Brown, MSc, Ph.D., Director, Computational Biology Infectious Disease and Oncology, GlaxoSmithKline

Traditionally, infectious and chronic diseases were separate silos in drug discovery. However, recent advances in genomics and bioinformatics are opening new dialogues between these fields. Understanding the microbiome in human health could provide new therapeutics for chronic diseases including respiratory and inflammatory diseases. Furthermore, new insights are emerging about the host-pathogen interactome. This presentation will discuss the opportunities and challenges for translation medicine using specific examples from our efforts.

11:35 Engineered Synthetic Peptides to Combat Infectious Diseases

César de la Fuente, Ph.D., Postdoctoral Associate, Synthetic Biology Group, Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology

Antibiotic-resistant infections are predicted to kill 10 million people worldwide per year by 2050, costing the global economy $100 trillion. Specific biologically inspired synthetic peptides are potent at preventing biofilm formation and eradicating pre-formed biofilms of the most dangerous and drug-resistant pathogens in our society. Moreover, lead peptides potentiate the activity of several classes of conventional antibiotics, and protect against otherwise lethal infections in several animal models.

11:50 Enjoy Lunch on Your Own

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