Targeting Gram-Negative Pathogens

Multidrug-resistant Gram-negative bacteria are one of the main challenges for the healthcare system and public health in general. Gram-negative bacteria have specific scientific problems, such as low permeability of the outer membrane that must be overcome, complicated and multiple resistance mechanisms, etc. Cambridge Healthtech Institute's 2^nd Annual Targeting Gram-Negative Pathogens conference will be taking place as a part of the 5^th Annual Re-Entering Antibacterial Discovery and Development Summit. It will be preceded by the more general Antibacterial Discovery and Development.

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

Final Agenda

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Thursday, September 27

11:50 am Conference Registration Open (Foyer)

12:20 pm Plenary Keynote Program (Constitution Ballroom)

2:00 Refreshment Break in the Exhibit Hall with Poster Viewing (Grand Ballroom)

Breaking Open Barriers

Constitution B

2:45 Welcome Remarks

Mana Chandhok, Conference Producer, Cambridge Healthtech Institute

2:50 Chairperson’s Opening Remarks

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

3:00 KEYNOTE PRESENTATION: Staphylococcus aureus mAbs in Development

Steven Projan, PhD, Former Senior Vice President, MedImmune; Beat the Reaper, LLC

There has been an increasing focus on the potential use of immunotherapies for bacterial infections (in what can best be called a back to the future approach as immune  anti sera were raised in large animals in the latter part of the nineteenth century with Emil von Behring winning first Nobel Prize for Physiology or Medicine).  Now in the 21st century the use of (fully human) monoclonal antibodies are being aggressively investigated in human clinical studies with Staphylococcus aureus being the prime pathogen being target.  Can the neutralization of one or a handful of the 300 plus virulence factors that Staph produces have a therapeutic or prophylactic effect?  The role of many of these virulence factors is evading the host response to infection but does the bacterium have an achilles heal? Preclinical data suggest this is the case with alpha toxin being one of the prime targets. 

EXTENDED-SPECTRUM BETA-LACTAMASE INHIBITORS: UPDATES

Constitution B

3:55 In vitro Activity of Imipenem-Relebactam against Gram-Negative ESKAPE Pathogens

Katherine Young, MS, Senior Principal Scientist, Richard T. Clark Fellow for Global Health, Infectious Diseases, Merck

Relebactam (formerly MK-7655) is an inhibitor of class A and C β-lactamases, including Klebsiella pneumoniaecarbapenemase (KPC), and is currently in clinical development in combination with imipenem-cilastatin. Using Clinical and Laboratory Standards Institute (CLSI)-defined broth microdilution methodology, we evaluated the in vitro activities of imipenem-relebactam, imipenem, and seven routinely tested parenteral antimicrobial agents against Gram-negative ESKAPE pathogens.

4:25 Refreshment Break in the Exhibit Hall with Poster Viewing (Grand Ballroom)

5:00 Innovation and Challenges in the Development of Beta-Lactamase Inhibitor Combinations

Michael N. Dudley, PharmD, FIDSA, Senior Vice President, CSO, Head of Infectious Disease Global Innovation, The Medicines Company

Development of new antibiotics for resistant gram-negative infections has been most successful by restoring the activity of proven β-lactam antibiotics through use of novel β-lactamase inhibitors. However, combination therapy presents challenges in getting the right partner agent as well as getting the PK-PD right. Examples of successes and failures will be discussed.

5:30 Restoring β-Lactam Efficacy against Methicillin-Resistant Staphylococci

Holly Sutterlin, PhD, Director of Biology, Prokaryotics

β-lactam antibiotics have served as the most impactful class of antibiotics but their efficacy has been eroded by the emergence of MRSA/E. To re-establish β-lactams as a standard of care therapy for MRSA/E infections, we are developing inhibitors of wall teichoic acid biosynthesis that exhibit bactericidal synergy in combination with broad-spectrum β-lactam antibiotics against diverse MRSA/E clinical isolates and show robust efficacy in a murine MRSA infection model.

6:00 Q&A with Speakers

6:30 Dinner Short Course Registration (Foyer)

9:30 Close of Day

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Friday, September 28

7:00 am Registration Open (Foyer)

7:30 Interactive Breakfast Breakout Discussion Groups - View Details 

Room: Back Bay A

Grab a cup of coffee and 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.

Table 16: Building an Understanding of Porin-Permeation in Gram-Negative Pathogens

Moderator: Ram Iyer, PhD, Principal Scientist (Bacteriology), Entasis Therapeutics, Inc.

• Addressing the knowledge gap for gram-negative pathogens
• Specific approaches, ie, TOMAS
• Identifying compounds that will disrupt the outer membrane

Table 17:Filling in the Gaps in the MDR Gram-Negative Pipeline

Moderator: Todd A. Black, PhD, Executive Director, Infectious Diseases, Basic Research, Merck Research Laboratories

• Narrow spectrum antibiotics
• Non-traditional / non-antibiotic approaches
• Challenges for clinical trial designs
• Diagnostic challenges of identifying the right patients and strategies
• Future steps

Gram-Negative Biologics

Constitution B

8:30 Chairperson’s Remarks

Antonio DiGiandomenico, PhD, Principal Scientist, Microbial Sciences, MedImmune

8:35 Immunotherapeutics Targeting Antibiotic-Resistant Pseudomonas aeruginosa

Antonio DiGiandomenico, PhD, Principal Scientist, MedImmune

P. aeruginosa is a major challenge for new antimicrobial drug discovery efforts because of its versatile lifestyle and ability to develop antibiotic resistance. This rise in resistance coupled with the dearth in discovery of new antibiotic classes requires development of alternative antimicrobials, such as pathogen-specific monoclonal antibodies (mAbs). In this presentation, I will introduce novel anti-Pseudomonal mAbs and discuss their mechanisms of action in multiple infection models.

9:05 Monoclonal Antibody Targeting the β-barrel Assembly Machine of Escherichia coli Is Bactericidal

Steven Rutherford, PhD, Scientist, Genentech

Folding β-barrel proteins into the outer membrane is essential in Gram-negative bacteria. We discovered an antibody, MAB1, that inhibits BamA, an outer membrane protein required for β-barrel assembly in Escherichia coli. MAB1 is bactericidal when the LPS is truncated and it inhibits β-barrel folding, induces periplasmic stress, and disrupts outer membrane integrity. MAB1 highlights the potential for new mechanisms of antibiotics to inhibit bacterial growth by targeting extracellular epitopes.

9:35 Next-Generation Approaches to Antibody Discovery for Treatment and Prevention of Infections Caused by Gram-Negative MDR Pathogens

Dante Ricci, PhD, Scientist, Early Research, Achaogen

Cases of neonatal infection are increasingly attributed to Gram-negative pathogens, with multi-drug-resistant Acinetobacter baumannii emerging as a major underlying cause of neonatal sepsis and consequent mortality. I will discuss the advantages of antibody-based approaches to prevention and treatment of Gram-negative infections, and describe a platform for the efficient identification of broadly cross-reactive anti-Acinetobacter mAbs that bind live bacteria and forestall infection.

10:05 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Competition Winner Announced (Grand Ballroom)

Anti-Gram Negative Small Molecules: Discovery And Development

Constitution B

10:45 Phenotypic Screening Strategies and Outcomes Directed towards Novel Gram-Negative Targets

Carl Balibar, PhD, Principal Scientist, Infectious Diseases, Merck

The emergence of multi-drug resistant bacteria is eroding the efficacy of existing antibiotics. Although genomics has greatly contributed to the identification of novel antibacterial targets, it has failed to exploit such targets to impact antibiotic discovery. Phenotypic screening remains the primary source for new antibacterial compounds; however, it is imperative to design screens with intent, target bias, and hit-prioritization strategies if high potential inhibitors and targets are to be discovered.

11:15 On the Design and Optimization of the Pyrrolocytosines

Erin M. Duffy, PhD, CSO, Melinta Therapeutics, Inc.

Our approach to the design of new antibiotics is unique, proprietary, and powerful, combining X-ray crystallography of the bacterial ribosome with a structure-based design process that we have refined over many antibiotic programs and that allows us to exploit existing as well as novel binding sites. The pyrrolocytosines represent completely novel small-molecule ribosome inhibitors from a de novo design effort targeting a validated but unexploited binding site, rationally designed to enhance bacterial influx and minimize bacterial efflux. The net result is robust coverage of ESKAPE pathogens as well as other urgent and serious threats on the CDC and WHO priority lists. Lead compounds are unaffected by resistance to current therapies, consistent with novel chemistry and mechanism, including ESBLs, KPCs, NDMs, mcr-1 and high-efflux-expressing P. aeruginosa. The structure-based design process has allowed us to problem-solve in the areas of in vitro activity, animal efficacy and preclinical safety. Herein, we present the dossiers of several pyrrolocytosine leads in preclinical development with credentials for addressing drug-resistant Neisseria gonorrhoeae, carbapenem-resistant Enterobacteriaceae and infections caused by pathogens across the full ESKAPE spectrum.

11:45 Enjoy Lunch on Your Own

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

Case Studies And Computational Approaches

Constitution B

1:55 Chairperson’s Remarks

Sharookh Bomi Kapadia, Senior Scientist, Infectious Diseases, Genentech

2:00 Bacterial Chemical Genomics: A Path of Ceased Resistance

Eric Brown, PhD, Professor, Biochemistry and Biomedical Sciences, McMaster University

Antibiotic drug resistance has reached crisis proportions, owing to a dearth of new antibiotics. In the Brown lab, we are developing chemical-genomic approaches with utility in exploring complex biology and enigmatic processes that are essential for bacterial survival. Efforts to date have resulted in new understanding, platforms, chemical probes and lead compounds for antibacterial research. The ultimate goal is to contribute fresh directions for new antibacterial therapies.

2:30 The Grim Reaper Is Lurking, What Matters More Death, Efficacy, or Safety?

Gary Eldridge, President & CEO, Sequoia Sciences, Inc.

Sepsis from UTI leads to more deaths annually than breast cancer. Sequoia Sciences is developing a vaccine to reduce the recurrences of UTI. Sequoia has evaluated its vaccine in women with and without a history of recurrent UTI. The vaccine has been well-tolerated and highly immunogenic, and elicited functional antibody responses. The results of these human studies, including preliminary clinical evidence of efficacy, and the design of future clinical studies will be presented.

3:00 Gram-Negative Lipoprotein Biosynthesis and Transport

Sharookh Bomi Kapadia, Senior Scientist, Infectious Diseases, Genentech

Antibiotic discovery for Gram-negative bacteria pose further challenges due to the impermeability of the asymmetric LPS-containing outer membrane. Here, we will discuss our efforts to better understand the bacterial lipoprotein synthesis and transport pathways and highlight the success and challenges associated with targeting them.

3:30 Bacterial Outer Membranes and Interactions with Membrane Proteins

Wonpil Im, PhD, Presidential Endowed Chair in Health, Science and Engineering, Professor of Biological Sciences and Bioengineering, Lehigh University

The outer membrane of Gram-negative bacteria is a unique asymmetric membrane bilayer: phospholipids in the inner leaflet and lipopolysaccharides in the outer leaflet. Its function as a selective barrier is crucial for the survival of bacteria, and it also renders gram-negative bacteria resistant to antibiotics. I will present our ongoing molecular modeling and simulation studies on various bacterial outer membranes and their interactions with outer membrane proteins.

4:00 Close of Conference

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