Part of Re-Entering Antibacterial Discovery and Development Summit

Antibacterial Discovery and Development

New discovery platforms, novel screens and approaches are vital for the discovery of new antibacterials and for ceasing the dangerous trend of multidrug microbial resistance. Cambridge Healthtech Institute's 5^th Annual Antibacterial Discovery and Development track will focus on the general, strategic issues and solutions that would allow new antibacterial development to move forward. The conference will be held as part of the 5^th Annual Re-Entering Antibacterial Discovery and Development Summit, and it will be followed by Targeting Gram-Negative Pathogens.

Advisors: Lynn Silver, LL Silver Consulting; Ruben Tommasi, Entasis Therapeutics; Joyce Sutcliffe, Formerly Tetraphase; Todd Black, Merck

Final Agenda

Wednesday, September 26

7:00 am Registration Open and Morning Coffee (Foyer)

Discovery Platforms: Natural Products And Genome Mining

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8:00 Welcome Remarks

Mana Chandhok, Conference Producer, Cambridge Healthtech Institute

8:05 Chairperson’s Opening Remarks

Zachary Zimmerman, PhD, CEO, Co-Founder, Forge Therapeutics, Inc.

8:10 KEYNOTE PRESENTATION: Culture Independent Discovery of New Antibiotics

Sean Brady, PhD, Associate Professor, The Laboratory of Genetically Encoded Small Molecules, Rockefeller University

Uncultivated microorganisms are an attractive source of potentially new antibiotics. Although there is no easy way to culture most environmental bacteria, it is possible to clone microbial DNA directly from environmental samples and study this DNA in the lab. We are using both functional and sequence-based metagenome screening strategies to identify antibiotics encoded by environmental bacteria. Antibiotics isolated in these studies will be discussed.

8:40 Forging Novel Classes of Antibiotics

Zachary Zimmerman, PhD, CEO, Co-Founder, Forge Therapeutics, Inc.

Forge Therapeutics is focused on developing small molecule, direct-acting, novel antibiotics that inhibit select metalloenzymes to treat infections caused from high priority drug-resistant bacteria. We are currently in late lead optimization for the first-ever non-hydroxamate inhibitor of LpxC, a bacterial Zn2+ hydrolase, for IV/oral treatment of urinary tract infection (‘FG-LpxC-UTI’).

9:10 Antimicrobials for Unmet Medical Needs

Kim Lewis, PhD, University Distinguished Professor, Biology; Director of Antimicrobial Discovery Center, Biology, Northeastern University

We identified compounds with no detectable resistance (Teixobactin, Novo29), and capable of killing persister cells (ADEP, lassomycin). ADC56 is a novel antimicrobial with coverage of Gram negative ESKAPE pathogens. Lyme disease is caused by B. burgdorferi, and we identified compounds acting selectively against this pathogen. Selectively killing pathobionts of the human microbiome is a new area for antimicrobial drug discovery, and we will discuss it as well.

9:40 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing (Grand Ballroom)

Discovery Platforms (CONT.)

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10:25 Mining the Actinomycete Armamentarium for Novel Antibiotics

Laurence E. Reid, PhD, CEO, Warp Drive Bio

Warp Drive Bio is deploying state-of-the-art, genome mining technologies to access natural molecules that have been historically “hidden” within microbes. We have built databases of genomic sequence from over 135,000 strains, encoding more than four million biosynthetic gene clusters. We are exploiting this database to isolate clusters that synthesize natural products that have not been previously studied and which have predicted antimicrobial activity. We will review our results to date regarding discovery of novel antimicrobials.

10:55 Near Future Prospects from Natural Products

Jose Ruben Tormo, PhD, Associate Area Head & Collection Manager, Chemistry, Fundacion MEDINA

Microbial natural products (NPs) are one of the most prolific sources of new leads for the discovery of novel antibiotics with a large number of molecules and analogs still today in the clinic. NPs present a unique chemical space with potency and selectivity being the result of an extended evolutionary selection. New integrated NPs discovery approaches are playing a key role in the identification of new molecules to be developed to fill the antibiotic pipeline.

11:25 Progress toward Selective Bacterial Protein Synthesis Antibacterials

Chad Testa, PhD, Vice President, Cūrza Global, LLC

Inspired by a natural product, Cūrza is developing antibiotics that selectively inhibit bacterial protein synthesis by acting on a clinically undrugged binding site on the ribosome. CZ-02s have excellent drug-like properties, do not show cross-resistance to other protein synthesis inhibitors (e.g., aminoglycosides, tetracyclines), are efficacious in murine E. coli infection models, have potent selective inhibition of bacterial protein synthesis and are not cytotoxic.

11:55 NEW: Fixing the Broken Antibiotics Business Model through Molecular Diagnostics

Andreas E. Posch, PhD, Founder & Managing Director, Ares Genetics GmbH

Ares Genetics’ vision is to revolutionize infectious disease diagnostics and therapeutics by translating success stories from treatment response prediction in cancer to microbial infections. To achieve this, Ares Genetics makes use of high-resolution Next Generation Sequencing (NGS) technology in combination with a proprietary pathogen and drug resistance biomarker database, ARESdb, for result interpretation. In this talk, we will present how ARESdb can be used for (a) diagnosing microbial infections and drug response prediction, as well as, (b) accelerating and informing antibiotic drug development across the product life cycle.

12:25 pm Session Break

12:35 Enjoy Lunch on Your Own

1:15 Refreshment Break in the Exhibit Hall with Poster Viewing (Grand Ballroom)

Alternative Therapies

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1:50 Chairperson’s Remarks

Neeraj (Neil) Surana, MD, PhD, Assistant Professor of Pediatrics, Molecular Genetics and Microbiology, Duke University

1:55 The Efficacy, Safety, and Tolerability of Gepotidacin (GSK2140944)

David Gardiner, Medicine Development Leader, Gepotidacin, GSK

Gepotidacin is a novel triazaacenaphthylene bacterial type II topoisomerase inhibitor which selectively inhibits bacterial DNA replication via a unique interaction on the GyrA subunit of bacterial DNA gyrase and ParC subunit of bacterial topoisomerase IV. Gepotidacin demonstrates in vitro activity against target pathogens resistant to current antibacterials, including fluoroquinolones. Gepotidacin shows efficacy in Phase 2 studies of ABSSSI and urogenital GC. Currently available preclinical and clinical data will be discussed.

2:15 Cloudbreak Antibody-Drug Conjugates for Treatment of MDR Gram Negative Bacterial Infections

James Levin, PhD, Director of Preclinical Development, Cidara Therapeutics

Cloudbreak ADCs physically link the pathogen and the immune component to eradicate pathogens via dual killing mechanisms. The engagement of specific innate immune system components confers potential to largely limit resistance development in target pathogens. Furthermore, by linking to an antibody Fc, ADCs possess extended half-lives to support once-weekly or bi-weekly dosing, making them well suited as immunotherapeutic agents to prevent and treat life-threatening multidrug-resistant Gram-negative infections.

2:35 Anti-Persister Strategy for the Treatment of Chronic, Recurrent Infections

Diane Joseph-McCarthy, PhD, Vice President, Translational Science, EnBiotix

Bacteria can enter into a persister state in response to various stresses including antibiotic treatment. In this metabolically dormant state, bacteria become tolerant or “transiently resistant” to antibiotics, which can lead to chronic, recurrent infections including persistent lung infections. Combinations of aminoglycosides with bacterial metabolites as proton-motive force enhancing potentiators were investigated. Pairwise combinations were screened using the time-kill method as well as biofilm assays. Eliminating bacterial persisters early may be a key to limiting further resistance and prolonging the lifetime of clinically important anti-infective agents.

2:55 Predicting Antibiotic Resistance with Bacterial Synthetic Biology

Ákos Nyerges, Project leader, Csaba Pál Lab, Synthetic and Systems Biology Unit, Hungarian Academy of Sciences

Forecasting resistance evolution at an early stage of drug development would be useful to identify less resistance-prone antimicrobials. To this aim, by building on synthetic biology, we developed a method (DIvERGE) that enables precise mutagenesis of drug targets, directly in pathogenic bacteria. This method allowed us to predict resistance evolution to antibiotics in a high-throughput manner. With DIvERGE, we also predicted probable resistance processes for antibiotics that are in clinical trials.

3:25 Refreshment Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced (Grand Ballroom)

Utilizing The Microbiome

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4:05 Exploiting Host–Microbiome Interactions to Treat Infectious Diseases

Neeraj (Neil) Surana, MD, PhD, Assistant Professor of Pediatrics, Molecular Genetics and Microbiology, Duke University

Although investigators are working on developing new antibiotics, the history of the past ~75 years suggests that success will be short-lived before confronting resistance. An alternative to drugs that directly target the pathogen is to augment the host immune response—in a pathogen agnostic manner—to better contain the infection. Improved understanding of cause-effect relationships between the microbiome and immunity will lead to new treatment modalities that complement conventional antibiotics.

4:35 Mining the Human Microbiome for Novel Gram-Negative Antibiotics

Jessica Ferreyra, PhD, Scientist, Biology, NGM Biopharmaceuticals

We have identified human microbiota-derived peptides that exhibit antimicrobial activity against human pathogens. Using two bioinformatics discovery pipelines, we identified 1,204 candidate antimicrobial products from 2,161 microbial genomes of bacteria associated with human gut, mouth, skin and urogenital sites.

5:05 Interactive Breakout Discussion Groups

Room: Constitution B

Join a breakout discussion group. These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations around a focused topic. 

Alternative Approaches to Treatment of Antibiotic-Resistant Pathogens

Moderator: Neeraj (Neil) Surana, MD, PhD, Assistant Professor of Pediatrics, Molecular Genetics and Microbiology, Duke University

• Microbiota-based therapies
• Phage-based therapies
• Vaccines-based therapies

Considerations for the Discovery Scientist

Moderator: James Levin, PhD, Director of Preclinical Development, Cidara Therapeutics

• What makes a good hit? What makes a good lead?
• How do you build a screening paradigm?
• How important is a target product profile? When should it be developed?
• What clinical development aspects should be considered in the discovery process? When should they be incorporated?

6:05 Welcome Reception in the Exhibit Hall (Grand Ballroom)

7:10 Close of Day

Thursday, September 27

7:30 am Registration Open and Morning Coffee (Foyer)

Funders And Accelerators

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8:00 Chairperson’s Remarks

Vikas Goyal, Associate, SR One

8:05 Replenishing and Enabling the Pipeline for Anti-Infective Resistance (REPAIR)

Aleks Engel, PhD, Partner, Novo Seeds, Nova Holdings

The REPAIR Impact Fund will invest $165m over 3-5 years in novel anti-infective therapies between lead optimization and end of Phase I.

8:25 Funding Opportunities with CARB-X

Kevin Outterson, Professor of Law, N. Neal Pike Scholar in Health and Disability Law, Boston University; Executive Director, CARB-X

CARB-X is a $455M public-private partnership funded by BARDA, the Wellcome Trust, and NIAID. We provide non-dilutive awards to companies to support innovative preclinical and Phase I development focused on priority bacterial pathogens.

8:45 How BARDA Is Addressing the Global Threat of Antimicrobial Resistance by Stimulating the End-to-End Research and Development of Novel Antibacterial Products

Mark Albrecht, Acting Branch Chief, Antibacterials Program, Biomedical Advanced Research and Development Authority

Since 2010, the Biomedical Advanced Research and Development Authority (BARDA) has addressed the rising threat of antimicrobial resistance by providing direct funding, access to core development and manufacturing services, and technical and business support to small biotechs and large, global pharmaceutical companies supporting the clinical development of new antibiotics. In 2016, BARDA, along with the Wellcome Trust and the National Institutes of Health, established the Combatting Antibiotic Resistant Bacteria Accelerator, or CARB-X, a public-private partnership managed by Boston University accelerating the preclinical research and development innovative products addressing the AMR threat. Together, BARDA is providing end-to-end support to developers of novel diagnostics, preventatives and treatments to beat back the growing global threat of antibacterial resistant bacteria.

9:05 Global Antibiotic Research and Development Partnership (GARDP)

François Franceschi, PhD,   Project Leader, Antimicrobial Memory Recovery and Exploratory Programme (AMREP), Global Antibiotic R&D Partnership (GARDP)