Past BAARN Meetings

Dr. Timothy Opperman

BIO I am the Director of Microbiology at Microbiotix, Inc., an anti-infective drug discovery company located in Worcester, MA, where I have worked on many early-stage antibiotic and anti-virulence projects over the last 18 years.

TALK TITLE Inhibitors of Type III secretion as an adjunctive anti-pseudomonal therapy

ABSTRACT Pseudomonas aeruginosa is an opportunistic pathogen that is one of the leading causes of pneumonia in hospitalized patients who require mechanical ventilation. These infections are difficult to treat due to the repertoire of virulence factors, and intrinsic- and acquired-resistance mechanisms that are deployed by P. aeruginosa during the infection process. To address this problem, we are developing a novel class of phenoxyacetamide (PhA) small molecules that inhibit the type 3 secretion system (T3SS), an important virulence factor that P. aeruginosa utilizes to establish infection and to facilitate dissemination to other tissues. The PhAs will be used as an adjunct to anti-pseudomonal antibiotics for treating hospital acquired pneumonia. In my presentation, I will describe the results of recent proof-of-principle studies for the lead PhA compounds.

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Dr. Peter Belenky

BIO After completing a double major in studio art and biochemistry at Brandeis University, Dr. Peter Belenky went on to earn his PhD in biochemistry from Dartmouth Medical School. Dr. Belenky was a Howard Hughes Medical Institute post-doctoral associate at Boston University and the Wyss Institute for Biologically Inspired Engineering at Harvard under the supervision of Dr. Jim Collins. Dr. Belenky joined the Department of Molecular Microbiology and Immunology at Brown University as an Assistant Professor in 2014. His work is focused on the responses of microbial communities and isolated microbes to external stressors such as antimicrobial agents. He is particularly interested in how the microbiome changes its functional profile in response to antibiotic stress. To answer these questions, he works with murine, human, and marine microbiomes. The long-term perspective of this work is that by understanding the links between host metabolism, microbial metabolism, and antibiotic efficacy, we can identify therapeutic methodologies to protect the microbiome from antibiotic-induced disruption. Other interests in the lab include the transfer and development of antibiotic resistance within complex microbial communities and microbiomes. The work in the Belenky lab is funded by the NIH, the DOD, and the USDA.

TALK TITLE Microbial and host metabolism regulate the susceptibility of the microbiota to antibiotic disruption

ABSTRACT Antibiotic exposure can lead to microbiome-related complications. In vitro data indicate that active bacterial metabolism is linked to antibiotic efficacy. Since the metabolic capacity of bacteria in the microbiome is modulated by diet and host metabolism, these factors must also regulate antibiotic-induced microbiome disruption. We utilize a multi-omic approach that combines whole microbiome metabolomics with shotgun metagenomics/metatranscriptomics to profile the impacts of microbial metabolism on antibiotic susceptibility. In the total microbiome of mice with and without metabolic perturbations, we found that reduced metabolic activity of specific taxa before and during treatment promotes antibiotic tolerance in the gut. We also found that inducing hyperglycemia in the murine host perturbs the gut metabolome and dramatically shifts how the community responds to antibiotic perturbation. Together this work indicates that host metabolism is a crucial driver of antibiotic-induced dysbiosis and that the modulation of metabolism in the gut can act as a therapeutic intervention to reduce complications of antibiotics. 

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Dr. Rida Mourtada

BIO Rida has over 9 years of research experience in the preclinical development of small peptide therapeutics in oncology & infectious disease. As a graduate student in the Walensky laboratory, Rida designed, synthesized, and validated the first stapled antimicrobial peptides (StAMPs) for in vivo use (Mourtada et al. Nat. Biotech., 2019). His passion for the development of new medicines led him to cofound Lytica Therapeutics, with Jim LaTorre and Loren Walensky, to bring the therapeutic potential of StAMPs to the clinic. Rida completed his Hon. BSc. and MSc. degrees at the University of Toronto and received his doctorate from the Harvard-MIT Program in Health Sciences and Technology at MIT.

TALK TITLE Stapled antimicrobial peptides: A new class of antibiotics to combat multidrug-resistant Gram-negative pathogens

ABSTRACT The rise of antimicrobial resistance is a major threat to healthcare systems around the globe and new agents that can stifle the surge in resistance are much needed. At Lytica, we have turned to one of nature’s many reserves of compounds with antibiotic properties, antimicrobial peptides (AMPs), and have been re-engineering these peptides into stable, potent drugs for human therapeutic use. By applying stapling technology to AMPs, we have developed a novel class of antimicrobials, which we call Stapled Antimicrobial Peptides (StAMPs). This unique class of peptides has a reinforced alpha-helical structure, enhanced biological activity, strong bacterial-membrane selectivity, and good stability. Moreover, StAMPs display potent lytic activity against highly drug-resistant bacterial pathogens including carbapenem-resistant P. aeruginosa and colistin-resistant A. baumannii. We are currently focused on translating the therapeutic potential of StAMPs for the treatment of pneumonia caused by drug-resistant Gram-negative pathogens.

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Dr. Aparna Ahuja

BIO Dr. Aparna Ahuja is currently the Chief Medical Officer at T2 Biosystems, providing leadership & strategic direction for all Medical,Clinical,Scientific and Regulatory activities. She is a Strong advocate of Patient and healthcareworker safety, with a career of almost 3 decades in laboratory medicine & Medical affairs in Med device-Invitro diagnostics. Dr Ahuja is the Scientific advisory board (SAB) member of PainCare labs, Chair and member of AACC Corporate advisory board (CAB), Chair AACC NJ section,Vice chair and member of CLSI expert panel, trained as auditor with CAP & ISO15189, an active member of various medical associations such as ASM, CAP, AMP, AACC, IDSA.

TALK TITLE Culture-Independent Tests for Rapid Detection of Sepsis-Causing Pathogens leading to Positive Healthcare Outcomes

ABSTRACT Sepsis is a complicated and challenging condition for physicians to diagnose. The greatest challenges for physicians is to rapidly diagnose or exclude a diagnosis of sepsis and implement targeted therapy without delay. Extended time from presentation to appropriate therapy remains a major contributor to poor patient outcomes and proliferation of antimicrobial resistance. Culture-independent tests have shifted the paradigm in species identification for blood stream infections. Current diagnostic tests for blood stream infections have limited sensitivity and extended time to identification of microbial pathogens causing sepsis. This session will explore how using novel culture-independent technology for the rapid identification of causative pathogens can lead to improved clinical and economic outcomes in septic patients.

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Dr. Joseph Ciolino

BIO Dr. Joseph Ciolino is a cornea fellowship trained ophthalmologist, clinician-scientist who is on full time staff at Massachusetts Eye and Ear/ Harvard Medical School. Dr. Ciolino has a multidisciplinary laboratory at Schepens Eye Research Institute that is focused on translational research that is supported by the National Institutes of Health, the Department of Defense, and other funding organizations. Dr. Ciolino's primary research is focused on developing a drug-eluting contact lens. The contact lens has demonstrated sustained release of a wide variety of medications for days to weeks at a time and been shown to be effective in multiple animal models. Dr. Ciolino’s clinical focus is on the treatment of cornea diseases, cataracts, and dry eye. He routinely performs cataract surgery, corneal crosslinking, and corneal transplantations, including endothelial keratoplasties (DMEK). Dr. Ciolino is the primary investigator for several clinical trials, including a 16 site double-masked study on the effect of corneal crosslinking the donor for the Boston type 1 keratoprosthesis. Dr. Ciolino also has an interest in clinical trial design and has served as a medical monitor for numerous pivotal clinical trials.

TALK TITLE Drug-eluting Therapeutic Contact Lenses for Bacterial Keratitis

ABSTRACT The mainstay therapy for bacterial keratitis remains antibiotic drops. Unfortunately, due to the rapid drainage and the physiological and anatomical barriers in the eye, eye drops have proven to be a very ineffective drug delivery system. This is particularly true for bacterial keratitis. Not surprisingly, many infections attributed to fluoroquinolone-resistant bacteria are simply not responsive to fluoroquinolone eye drops, even when given hourly. A major unmet need for the treatment of bacterial keratitis is a method of sustained antibiotic delivery to the cornea that avoids the peak and trough drug tissue levels associated with eye drops. Therefore, we developed a drug-eluting therapeutic contact lens (TCL) that incorporates a thin drug-polymer film within the periphery of a contact lens using biocompatible materials, which enables the sustained release of drugs at elevated rates. Using the TCL, we have shown that we can deliver drugs into the cornea at levels that far exceeds eye drops, even when given hourly. Using the TCL, we hope to study the hypothesis that the use of antibiotics of last resort (e.g. vancomycin, linezolid) could be limited through more effective means of drug delivery that increase drug tissue concentrations of 1^st or 2^nd line antibiotics, such as fluoroquinolones (FQ). In addition to improved efficacy, the TCL can also address the poor adherence that is associated with eye drops.

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Dr. Ji-Xin Cheng

BIO Ji-Xin Cheng is currently the Moustakas Chair Professor of Photonics at Boston University. He attended University of Science and Technology of China (USTC) from 1989 to 1994. From 1994 to 1998, he carried out his PhD study on bond-selective chemistry at USTC. As a graduate student, he worked as a research assistant at Universite Paris-sud (France) on vibrational spectroscopy and the Hong Kong University of Science and Technology (HKUST) on quantum dynamics theory. After postdoctoral training on ultrafast spectroscopy at HKUST, he joined Sunney Xie’s group at Harvard University as a postdoc, where he spearheaded the development of CARS microscopy that allows high-speed vibrational imaging of cells and tissues. Cheng joined Purdue University in 2003 as Assistant Professor in Weldon School of Biomedical Engineering and Department of Chemistry, promoted to Associate Professor in 2009 and Full Professor in 2013. He joined Boston University as the Inaugural Theodore Moustakas Chair Professor in Photonics and Optoelectronics in summer 2017. Cheng and his team has been constantly at the most forefront of chemical imaging in innovation, discovery, and clinical translation. For his contributions to the field of vibrational spectroscopic imaging, Cheng received the 2020 Pittsburg Spectroscopy Award from the Spectroscopy Society of Pittsburg, the 2019 Ellis R. Lippincott Award from OSA, Society for Applied Spectroscopy, Coblentz Society, and the 2015 Craver Award from Coblentz Society. Cheng is authored in over 280 peer-reviewed articles with an h-index of 84 (Google Scholar). His research has been supported by over 30 million ($) funding from federal agencies including NIH, NSF, DoD, DoE and private foundations including the Keck Foundation. In 2014 He co-founded Vibronix Inc which has the mission of saving lives through medical device innovations. In 2019, he co-founded Pulsethera aiming to kill superbugs by photolysis of intrinsic chromophores. Cheng is a Fellow of Optical Society of America, a Fellow of American Institute of Medicine and Biological Engineering, and associate editor of Science Advances.

TALK TITLE Eliminating Drug-Resistant Bacteria and Fungal Infections via photolysis of Intrinsic Chromophores

ABSTRACT Antibiotic resistance kills an estimated 700,000 people each year worldwide, and study predicts that this number could rise to 10 million by 2050 if efforts are not made to curtail resistance (Nature, 2017, 543:15). Yet, the pace of resistance acquisition from mutation in pathogens is faster than clinical introduction of new antibiotics. This severe situation calls for an urgent need of developing unconventional ways to combat the resistance. To tackle this challenge, we are developing a novel phototherapy platform for fighting against a broad spectrum of drugresistant infections. In particular, we have found that some intrinsic chromophores are probe to photobleaching. Importantly, these chromophores are virulence factors or essential for bacteria and fungi to survive in a stressed condition. Thus, photo-destruction of these intrinsic chromophores sensitizes the bacteria and fungi to attack by administered hydrogen peroxide, immune cells, or conventional antibiotics. Unlike the photodynamic therapy, this approach does not need photodynamic agents.

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Dr. Matthew Henn

BIO Matthew Henn is the Executive Vice President and Chief Scientific Officer of Seres Therapeutics. He has over 25 years of combined research experience in microbial ecology, genomics and bioinformatics that spans both environmental and human disease applications. He has been involved in the discovery and clinical development of multiple microbiome therapeutics including all of Seres’ product candidates and has authored over 65 peer-reviewed publications. His research has focused on microbial physiology and the functional role of microbes in both environmental and human disease applications, and on the development of genomic and functional tools to study microbial systems. Prior to helping launch Seres in 2012, he was the Director of Viral Genomics and Assistant Director of the Genome Sequencing Center for Infectious Diseases at the Broad Institute of MIT and Harvard. He has served on various NIH working groups on antimicrobial resistance and microbiome research, as a scientific advisor for NIH’s Viral Pathogen Bioinformatics Resource Center, and as an ad-hoc reviewer and editor of various peer-reviewed journals. He currently serves on the scientific advisory board of Growcentia, Inc., an agricultural microbiome company. Dr. Henn earned his B.S. in ecology and evolutionary sciences from the University of New Hampshire and his Ph.D. from the University of California at Berkeley, where he was a NASA Earth Systems Sciences Fellow, and trained as an NSF Postdoctoral Fellow at Duke University.

TALK TITLE Live microbiome therapeutics for transforming the prevention and treatment of antimicrobial resistant infections

ABSTRACT The global rise in antimicrobial resistant (AR) bacteria is an urgent crisis with limited therapeutic options. The gastrointestinal microbiota is the first line of defense against colonization with AR bacteria, particularly in vulnerable hosts with frequent antibiotic exposure. Seres is developing novel therapeutics that harness the microbiome and seek to transform the prevention and treatment of AR bacterial infections. In a double-blind Phase 3 trial of rCDI patients investigational microbiome therapeutic SER-109 was superior to placebo in reducing CDI recurrence at week 8 post clinical resolution on standard of care antibiotics (12.4% versus 39.8%, respectively, p=0.001 95% CI 0.18-0.58). Herein, we report the impact of SER-109 on the prevalence of AR genes compared to placebo in the gut. Additionally, Seres is developing SER-155 an investigational cultivated microbiome therapeutic intended to reduce the risk of infection and bacteremia caused by VRE and CREin immunocompromised adults undergoing allogeneic HSCT. Preclinical assessments in vitro and in vivo support a model in which SER-155 nutrient competition may contribute to reducing CRE and VRE carriage restoring colonization resistance, and additionally maintaining epithelial barrier integrity to reduce translocation events. A Phase 1b study evaluating SER-155 in allogeneic HSCT patients for the reduction of bacteremia and acute GVHD has cleared an IND with the FDA.

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Dr. Alita Miller

BIO Alita Miller is Vice President and Head of Biology at Entasis Therapeutics, a biotech located outside of Boston dedicated to the discovery and development of novel antibacterial agents to treat serious infections by resistant Gram-negative bacteria. At Entasis, Alita oversees both preclinical biology and developmental microbiology research. She has nearly 20 years of experience in antibacterial research, first at Pfizer where she led both large and small molecule discovery projects and then at AstraZeneca, where she was Head of Microbial Genetics and Genomics. Alita obtained a BA in Chemistry from Kalamazoo College and a PhD in Biochemistry & Molecular Biology from the University of Chicago. Her postdoctoral training was in the DiRita lab at the University of Michigan characterizing the molecular drivers of pathogenesis in Streptococcus pyogenes. Alita’s current research interests include novel approaches to antibacterial discovery, including new ways of characterizing small molecule permeation and accumulation in bacterial pathogens.

TALK TITLE Discovery of ETX0462: Rational design of a new antibiotic class for drug-resistant infections

ABSTRACT The diazabicyclooctane (DBO) class of compounds includes serine β-lactamase inhibitors such as avibactam, relebactam and the Entasis phase 3 clinical candidate, durlobactam. Some DBOs also inhibit Penicillin Binding Protein 2 (PBP2), leading to potent antibacterial activity. However, this is also accompanied with key liabilities including a high spontaneous frequency of resistance (FOR) in vitro and lack of efficacy in vivo, thereby rendering them unsuitable for further development. Entasis hypothesized that conversion of a PBP2-selective DBO into a potent PBP1 and PBP3 inhibitor would be an effective solution to this problem. We identified four key features needed for a DBO to covalently link to the Pa PBP3 active site serine. Although the target spectrum of an initial lead was successfully re-engineered to gain in vivo efficacy and lower FOR, its ability to permeate across bacterial outer membranes was insufficient for further advancement. We then expanded our strategy to include optimization of porin permeation properties concomitant with biochemical potency in the lead optimization stage. This led to the discovery of ETX0462, a novel, single agent DBO, with potent PBP1 and PBP3 inhibition, excellent in vitro and in vivo activity against Pseudomonas aeruginosa plus all other Gram-negative ESKAPE pathogens, Stenotrophomonas maltophilia and biothreat pathogens. These results support further development of ETX0462 as a first-in-class single agent DBO to treat multidrug-resistant Gram-negative infections.

Session 1: New Diagnostics

Gowtham Thakku (MGH/Broad/HMS)

Rapid and accurate diagnosis of infections is fundamental to individual patient care as well as broader public health surveillance. Nucleic acid detection has emerged as a crucial method for pathogen identification, but may necessitate a diagnostic hypothesis (such as with amplification-based tests) or require complex infrastructure (as with next generation sequencing). Here, we present a high-throughput system that enables rapid identification of large panels of pathogens and resistance markers with significantly lower operating complexity than sequencing based methods. Our system utilizes two recently developed technologies: (1) Modular CRISPR-Cas13 based nucleic acid sensing that enhances sensitivity and specificity when combined with traditional amplification methods; and (2) A droplet microfluidics system that enables thousands of spatially multiplexed detection reactions at nanoliter volumes. We develop a method to identify unique pathogen genomic targets and demonstrate species-level detection of genomic DNA from nearly fifty clinically relevant bacterial species, all in a single assay. The system can easily be adapted for the detection of any large panel of nucleic acid targets and we also demonstrate the ability to detect multiple key bacterial resistance genes. The compatibility of CRISPR-Cas13 with freeze-drying opens up the possibility of a portable, highly multiplexed assay with broad developing world applications.

Dr. Roby Bhattacharyya, MD PhD (MGH/Broad/HMS)

Current growth-based antibiotic susceptibility testing (AST) is too slow to guide antibiotic selection in real time, leading to an overuse of empiric broad-spectrum antibiotics. We recently showed that antibiotic-induced transcriptional signatures distinguish susceptible from resistant bacteria and can be detected using a simple multiplexed hybridization assay, providingphenotypic AST within hours instead of days. This assay relies on the principle that susceptible cells become stressed upon brief antibiotic exposure, eliciting transcriptional changes within minutes that distinguish them from unharmed resistant cells. Here we report that, for three major antibiotic classes (beta-lactams, fluoroquinolones, and aminoglycosides), the same gene signatures we previously optimized for one member of each antibiotic class generalize to all members of that class. Furthermore, we show proof-of-concept that transcriptional profiling also predictsantifungal susceptibility in the eukaryotic pathogen Candida albicans. Together, these findings demonstrate the potential of transcriptional assays as a possible pan-microbial approach to rapid phenotypic AST on a unified platform that can also detect genotypic resistance determinants.

Dr. Karel Brinda, PhD (HSPH/HMS)

Surveillance of drug-resistant bacteria is essential for healthcare providers to deliver effective empirical antibiotic therapy. However, traditional molecular epidemiology does not typically occur on a timescale that could affect patient treatment and outcomes. We present a method called ‘genomic neighbor typing’ for inferring the phenotype of a bacterial sample by identifying its closest relatives in a database of genomes with metadata. We show that this technique can infer antibiotic susceptibility and resistance for both Streptococcus pneumoniae and Neisseria gonorrhoeae. We implemented this with rapid k-mer matching, which, when used on Oxford Nanopore MinION data, can run in real time. This resulted in the determination of resistance within 10 min (91% sensitivity and 100% specificity for S. pneumoniae and 81% sensitivity and 100% specificity for N. gonorrhoeae from isolates with a representative database) of starting sequencing, and within 4 h of sample collection (75% sensitivity and 100% specificity for S. pneumoniae) for clinical metagenomic sputum samples. This flexible approach has wide application for pathogen surveillance and may be used to greatly accelerate appropriate empirical antibiotic treatment.

Dr. Ramy Arnaout, MD PhD (AstraDx/BIDMC/HMS)

Antimicrobial susceptibility testing (AST) is a critical component of caring for patients with bacterial infections but typically takes a day or more, with the delay contributing to significant morbidity and mortality. We have developed an optics-based platform that detects growth across a variety of bacterial species and strains in approximately 30 minutes, with determination of susceptibility vs resistance. Advantages include a phenotypic readout and the ability to test multiple antimicrobials in parallel, in full doubling-dilution series, with replicates for statistical rigor, using inexpensive, commercially-available disposables and at-will inkjet printing functionality for primary specimen analysis, if preferred.

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Session 2: New Therapeutics

Dr. Cheleste Thorpe, MD (Tufts School of Medicine)

Secondary bile acid production from a diverse commensal flora may be a critical factor in preventing recurrence of Clostridioides difficile infection (CDI), by inhibiting organism growth and limiting amounts of pro-germinant primary bile acids. Ridinilazole, a novel narrow spectrum drug for CDI, demonstrated superior sustained clinical response compared to vancomycin in a Phase 2 trial. Longitudinal stool sampling in this trial allowed us to assess microbiota and bile acids differentially present in subjects during/after treatment, and compare within treatment arms. Vancomycin treatment resulted in changes in a broad spectrum of phyla, with decreases in Bacteroidetes, Firmicutes and Actinobacteria and increases in Enterobacteriaceae. In contrast, ridinilazole’s effect was confined to only several of the Firmicutes. Stool bile acid compositions were significantly different between ridinilazole-treated and vancomycin-treatedsubjects at end-of-treatment. In vancomycin-treated subjects, stool composition became dominated by conjugated primary bile acids, with decreased levels of secondary bile acids compared with baseline. In contrast, ridinilazole had minimal effects on bile acids at end-of-treatment; over time these subjects recovered a bile acid composition more similar to a healthy control group. Comparing subjects who recurred to those who did not, a statistically significant difference was observed in total secondary bile acids and in the ratio of total conjugated to secondary bile acids at end-of-treatment. In conclusion, microbiota-preserving CDI treatment also preserves bile acid composition, which may decrease the likelihood of recurrence.

Dr. Bree Aldridge, PhD (Tufts School of Medicine)

Mycobacterium tuberculosis infects billions of people worldwide and remains difficult to treat, requiring lengthy multidrug therapies to cure. Design of new multidrug therapies for TB is challenging because it has not been practical to systematically measure drug combination effects. We have recently developed a quantitative framework to efficiently measure, analyze, and predict pairwise and high-order drug interactions, allowing us to prioritize combinations for animal studies. We leverage the efficacy and ease-of-use of our assay to systematically measure drug combinations in multiple growth conditions. We aim to use this data compendium to more precisely map in vitro to in vivo efficacy data, account for the heterogeneity of tuberculosis infection, and formulate more effective drug regimens. The toolswe develop for drug regimen design in tuberculosis are broadly application to other difficult to treat infections.

Dr. Johan Paulsson, PhD (Harvard Systems Biology)

Populations of pathogenic bacteria can display great variability in their antibiotic tolerance, where a few cells can survivedrugs and repopulate their hosts post-treatment. Many such behaviors have been hard to study because they are rare and transient. I will present platforms for directly observing persister dynamics and heteroresistance phenomena, as well as some clues about underlying mechanisms. I will also discuss recent technological advances in handling bacterial cells for both biophysical characterizations and drug screens.

Dr. Ruben Tommasi, PhD (Entasis Therapeutics)

Antibacterial drug discovery is challenging and riddled with failures in our attempts to identify inhibitors with novel modesof actions. This has been discussed for many years and to date there has been no clear reason as to why so many programs on genetically validated targets have failed to render candidates to the clinic. One key reason why biochemical activity does not translate into microbiological activity is the challenge of cell permeation, in particular in the Gram-negative pathogens. While novel approaches to address this key need are being actively worked on, with sights on generating ‘rules for permeation’ for these challenging pathogens, we are still far from being able to routinely design molecules with permeation in mind. We present here our recent experience on optimizing covalent inhibitors of the well-validated targets of the β-lactam class of antibiotics, the Penicillin-Binding Proteins (PBPs). While seeking to enhance the efficacy of the diazabicyclooctane class of inhibitors towardsbroader spectrum PBP activity, we identified a dramatic methyl effect on the Pseudomonas aeruginosa PBP3 kinetic parameters. Unfortunately, this beneficial effect on biochemical potency came along with detrimental consequences for microbiology which werequite unexpected. Our efforts to overcome these challenges and learnings derived thereof will be shared in this presentation.

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Session 3: Alternative Therapeutics & Entering the Market

Dr. Su Chiang, PhD (CARB-X)

CARB-X is a global non-profit partnership dedicated to accelerating antibacterial research to tackle the global rising threat of drug-resistant bacteria. With up to US$480 million to invest in 2016-22, CARB-X funds the best science from around the world. The CARB-X portfolio is the world’s largest early development pipeline of new antibiotics, vaccines, rapid diagnostics, and other products to prevent, diagnose, and treat life-threatening bacterial infections. CARB-X is led by Boston University and funded by the US Department of Health and Human Services Biomedical Advanced Research and Development Authority (BARDA), the Wellcome Trust, Germany’s Federal Ministry of Education and Research (BMBF), the UK Government’s Global Antimicrobial Resistance Innovation Fund (UK GAMRIF), the Bill & Melinda Gates Foundation, and receives in-kind support from the US National Institute of Allergy and Infectious Diseases (NIAID).

Dr. Silvia Caballero, PhD (Vedanta Biosciences)

Current treatment options for infections with multidrug-resistant organisms (MDRO), such as carbapenem-resistant Enterobacteriaceae (CRE), rely on toxic, narrow-spectrum antibiotics with known resistance. MDRO gastrointestinal (GI) colonization often precedes infection in highly susceptible patient populations and is associated with a 5-10-fold infection risk, suggesting that MDRO intestinal decolonization could be a potential strategy to prevent infection with these organisms.Because microbiota disruption is a major risk factor for MDRO colonization, there has been increasing interest in fecal microbiota transplantation (FMT). Although clinical experience indicates that FMT is effective, MDRO decolonization rates range widely from 30-90%. This variability underscores the need for a uniform microbiome-based product that has robust efficacy and can be produced and administered in a standardized manner, circumventing FMT’s associated safety concerns. Vedanta is addressing the critical need for novel therapeutics to prevent MDRO infection by developing VE707, a live biotherapeutic product (LBP) consisting of well-characterized, beneficial gut bacteria that can eliminate intestinal carriage of MDROs, restore a healthy microbiota and prevent infection and colonization recurrence.

Cristina Larkin (Spero Therapeutics)

There are a lot of misconceptions about commercial sustainability in the antibiotic space. Because of some of the recent bankruptcies in the space it has caused the market to question the sustainability of antibiotic companies. The journey to building a sustainable model includes a hero product, frequently updated expert advice guidelines, value based pricing, reimbursement reform and multiple options for capital until breakeven. The talk will include an overview of high unmet need areas, learnings from the oncology market and solutions for reimbursement reform. A healthy ecosystem of biotech, payers, KOLs, investors, Pharma and government can help us bridge to sustainability and ultimately build a sustainable commercial model.

Dr. Minmin (Mimi) Yen, PhD MPH (PhagePro)

In low-and middle-income countries (LMIC), the threat of antibiotic resistance is growing at an alarming rate. Widespread ease of access has increased antibiotic consumption rates and clinical misuse. These regions are also more likely to lack clean water and have issues with sanitation and hygiene, contributing to high numbers of diarrheal disease. LMIC are balancing the burdens of infectious and noncommunicable diseases, stretching their already low resources. Phages provide an affordable, convenient alternative to prevent and treat bacterial diseases, particularly in areas where logistical infrastructure is poor. PhagePro has developed a phage cocktail, ProphaLytic-Vc (PVC), that is targeted towards the causative agent of cholera Vibrio cholerae. Cholera is an acute diarrheal disease that causes rapid dehydration; death can occur as quickly as 12 hours. In addition to being endemic in 51 countries, cholera epidemics often occur in the aftermath of natural disasters or during humanitarian crises such as war. It is rapidly becoming extensively drug resistant, in part due to the use of antibiotic prophylaxis as a way to contain the outbreaks. PVC is intended as an antibiotic alternative to provide immediate protection for those most at-risk for cholera, including household contacts in endemic settings and refugee camps in epidemic settings. To be of most use, PhagePro is developing PVC as a solid formulation to be stable in hot and humid conditions, easing the burden of cold-chain logistics for mass distribution in emergency conditions. Phages have the potential to be transformative global health interventions, if the context for their use in LMIC is taken into account duringproduct development. With a disproportionate number of antibiotic-resistant-related deaths predicted to occur in LMIC, phages are uniquely suited as a solution to this public health threat.