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Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 599.95K | Year: 2012

DESCRIPTION (provided by applicant): The goal of this project is to discover novel antibiotics by activating the silent biosynthetic operons of Actinobacteria. Whole genome sequencing of many Actinobacteria showed that there are 10-20 times more operons coding for secondary metabolites than known compounds in a given species. This opens an attractive opportunity to access a large untapped source of new antibiotics. Genetic engineering has been used to turn on silent operons in Actinobacteria, leading to production of secondary metabolites. However, the pace at which engineered operons are activated is very low, less than ten metabolites a year are being reported based on this approach. We reasoned that mutagenesis of isolates that do not produce antimicrobials in vitro will relieve silent operons from regulatory constraints, and screening will then identify the producing mutants. Our preliminary data showed that the approach works surprisingly well, turning over half of the inactive organisms into antibioticproducers. The method is scalable, and we recently identified two potentially novel antimicrobials using this approach. In Phase I, we will mutagenize/screen 2,000 inactive strains for antibiotic production, aiming to obtain new, potentially useful antimicrobials. Biological and chemical dereplication will indicate compounds with potential novelty. We will give priority to broad spectrum compounds with activity against difficult to treat gram-negative pathogens. The antimicrobials will be tested for potency, spectrum, specificity of action and cytotoxicity, and th structure of compounds that pass validation will be determined. Finding 2-3 antimicrobials with novel chemistry will serve as proof-of-principle for this approach. These findings will provide a solid basis for a large-scale drug discovery effort in Phase II. PUBLIC HEALTH RELEVANCE: The overall goal of the project is to develop a simple and efficient method to discover novel antibiotics to combat drug-resistant pathogens that pose a serious health threat in the US and around the world. Novel approaches for discovering antibiotics are desperately needed as the drug pipeline for treating these dangerous human infections continues to diminish.


Grant
Agency: NSF | Branch: Standard Grant | Program: | Phase: | Award Amount: 147.28K | Year: 2013

This Small Business Innovation Research (SBIR) Phase I project will develop a new platform technology to exploit previously inaccessible microbial diversity to discover novel broad-spectrum antibiotics. The project focuses on symbioses between marine invertebrates and microorganisms known to be rich sources of novel bioactive compounds with potential therapeutic value. Microbial symbionts have long been suspected to be the actual producers of such compounds. They, and other microorganisms in general, remain largely unexplored because over 99% of them cannot be cultivated in the laboratory. Recovery of cultivable microorganisms from the sea is especially poor (0.1 to 0.01%) making the ?missing? marine species particularly attractive. The company employs a radically new method for in situ cultivation of previously uncultured microorganisms that significantly raises the cultivability of environmental bacteria, from <1% using traditional technologies to >20%. In Phase I, the company will adopt and optimize this method to access microorganisms specifically from marine symbioses, isolate novel microbial species from marine sponges and corals, and explore their antimicrobial properties. The principle intellectual merit and innovation of this proposal is in focusing on an essentially novel source of antimicrobials, microbes living in association with marine invertebrates, and the use of a novel method to grow these microbes.

The broader impact/commercial potential of this project stems from an increasing need for new antibiotics with new modes of action that are not susceptible to current resistance mechanisms. Agencies such as the Antimicrobial Availability Task Force of the Infectious Diseases Society of America and the World Health Organization have publicized the urgency of the resistance problem and the lack of forthcoming antibiotics in development. The multiple antibiotic-resistant bacteria are the exact pathogens that the company is targeting. Although big Pharma has largely abandoned their antibiotic discovery programs, they remain interested in acquiring new viable antibiotics. The global market for antibiotics is over $25 billion. Top earners, such as Levaquin (Floxin), Zosyn, and Augmentin have 2008 sales over $1 billion, with significant resistance already observed to all three. There is also an acute, unmet need and market even for narrow-spectrum antibiotics. Their commercial value and societal importance cannot be overstated. Of particular importance is that the proposed research will not only lead to a selection of novel antimicrobials, but to a new technology platform forming a whole new pipeline of new therapeutics.


Grant
Agency: National Science Foundation | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 147.28K | Year: 2013

This Small Business Innovation Research (SBIR) Phase I project will develop a new platform technology to exploit previously inaccessible microbial diversity to discover novel broad-spectrum antibiotics. The project focuses on symbioses between marine invertebrates and microorganisms known to be rich sources of novel bioactive compounds with potential therapeutic value. Microbial symbionts have long been suspected to be the actual producers of such compounds. They, and other microorganisms in general, remain largely unexplored because over 99% of them cannot be cultivated in the laboratory. Recovery of cultivable microorganisms from the sea is especially poor (0.1 to 0.01%) making the ?missing? marine species particularly attractive. The company employs a radically new method for in situ cultivation of previously uncultured microorganisms that significantly raises the cultivability of environmental bacteria, from<1% using traditional technologies to>20%. In Phase I, the company will adopt and optimize this method to access microorganisms specifically from marine symbioses, isolate novel microbial species from marine sponges and corals, and explore their antimicrobial properties. The principle intellectual merit and innovation of this proposal is in focusing on an essentially novel source of antimicrobials, microbes living in association with marine invertebrates, and the use of a novel method to grow these microbes. The broader impact/commercial potential of this project stems from an increasing need for new antibiotics with new modes of action that are not susceptible to current resistance mechanisms. Agencies such as the Antimicrobial Availability Task Force of the Infectious Diseases Society of America and the World Health Organization have publicized the urgency of the resistance problem and the lack of forthcoming antibiotics in development. The multiple antibiotic-resistant bacteria are the exact pathogens that the company is targeting. Although big Pharma has largely abandoned their antibiotic discovery programs, they remain interested in acquiring new viable antibiotics. The global market for antibiotics is over $25 billion. Top earners, such as Levaquin (Floxin), Zosyn, and Augmentin have 2008 sales over $1 billion, with significant resistance already observed to all three. There is also an acute, unmet need and market even for narrow-spectrum antibiotics. Their commercial value and societal importance cannot be overstated. Of particular importance is that the proposed research will not only lead to a selection of novel antimicrobials, but to a new technology platform forming a whole new pipeline of new therapeutics.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 746.21K | Year: 2016

This project studies the structure activity relationship SAR of the newly discovered antibiotic teixobactin with the goal of delivering a candidate that has development advantages over the parent compound Teixobactin is an unusual depsipeptide that is the first member of a novel class of peptidoglycan synthesis inhibitors Teixobactin targets lipid II peptidoglycan precursor and lipid III teichoic acid precursor It binds to undecaprenyl PP sugars which are not known to be modified as opposed to a later lipid II d ala d ala modifiable form targeted by vancomycin This unique mode of action binding to two targets neither of which is a protein suggests that resistance will be very difficult to develop To date no resistance has been detected Teixobactin has potent activity against a broad range of Gram positive bacteria S aureus MRSA S pneumoniae B anthracis M tuberculosis E faecalis and E faecium It is active against resistant forms of these pathogens including vancomycin resistant enterococci Teixobactin was highly efficacious in a murine MRSA septicemia and thigh infection models and against S pneumoniae in a lung infection model Teixobactin itself is moving into development However studies of teixobactin have identified a property of the compound that can be improved Teixobactin has a tendency to gelate in serum which may present a problem depending on the dosing regimen required for humans e g if higher serum concentrations of the drug are required for humans than mice and has presented a challenge in administering the compound at higher doses in preclinical studies Gelation of small peptides is a well known phenomenon that has been successfully addressed with medicinal chemistry optimization We will conduct a medicinal chemistry campaign to gain a good understanding of the SAR of the molecule and use this information to produce analogs that do not gelate but retain potent antibacterial properties Early proactive understanding of the SAR of teixobactin would also guide the design of new analogs that could address additional issues that may come up during the development of teixobactin itself An evaluation of the effect of modifying a variety of positions in the molecule will be conducted through both semisynthetic and fully synthetic approaches Several analogs have already been produced by both approaches which demonstrate the feasibility of the approach Multiple analogs will be produced and tested for antibacterial activity lipid II binding gelation and in vitro ADMET properties Three analogs with reduced gelation but favorable in vitro properties will be selected for mouse studies including MTD PK and efficacy against MRSA in the thigh infection model The results of this project will produce a therapeutic lead candidate ready to enter further development including IND enabling studies Narrative New antibiotics are needed to combat an impending public health disaster that annually causes million illnesses in the United States alone The proposed study focuses on understanding the structure activity relationship of a newly discovered antibiotic with the goal of developing an antibiotic against multidrug resistant infections


Patent
NovoBiotic Pharmaceuticals, LLC | Date: 2015-11-30

The invention relates generally to novel antibiotics and their analogs, to processes for the preparation of these novel antibiotics, to pharmaceutical compositions comprising the novel antibiotics; and to methods of using the novel antibiotics to treat or inhibit various disorders.


Patent
NovoBiotic Pharmaceuticals, LLC | Date: 2015-07-01

The present invention relates generally to novel depsipeptides, to methods for the preparation of these novel depsipeptides, to pharmaceutical compositions comprising the novel depsipeptides; and to methods of using the novel depsipeptides to treat or inhibit various disorders.


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 2.97M | Year: 2013

DESCRIPTION provided by applicant The overall goal of this project is to discover novel antibiotics to combat important drug resistant pathogens We are running out of treatment options for pathogens such as S aureus MRSA vancomycin resistant Enterococci VRE multidrug resistant P aeruginosa A baumannii ESBL and New Delhi metallo b lactamase producing Enterobacteriaceae and M tuberculosis Only novel antibiotics have been introduced in the past thirty years linezolid daptomycin and fidaxomicin Linezolid and fidaxomicin were discovered in the s but did not appear sufficiently attractive at the time With this pace of discovery it is not surprising that resistance is on the rise It is becoming increasingly apparent that the bottleneck in antibiotic discovery is the lack of good starting compounds Not a single drug came out of HTS of synthetic compound libraries Secondary metabolites produced by actinomycetes have been the main source of antibiotics but this resource was over mined At the same time there is a potentially very large untapped source of natural products previously uncultured bacteria that make up the vast majority of all bacterial species Slow growing species that require months to form colonies on a Petri dish are an important component of this majority We reasoned that slow growers may actually represent dormant forms of bacteria and will rapidly grow upon reinoculation The majority of slow growers can indeed be rapidly cultured upon reinoculation and many of the isolates represent previously unknown species and genera In Phase I we developed a method to simultaneously isolate and culture slow growers by placing individual cells in wells of a microtiter plate Screening of these isolates produced new antimicrobial compounds including Novo that acts specifically against M tuberculosis The target of Novo is the ClpC subunit of the essential mycobacterial ClpP protease Novo has low cytotoxicity favorable tolerability and blood levels in mice We will examine efficacy of Novo in mouse models of tuberculosis Further development of our three novel antibacterials are a major focus of Phase II However we recognize that only a small fraction of leads makes it to a drug Thus we will also undertake a large scale discovery effort to identify additional antibacterials which will enter validation as they become available Novel compounds will be examined for spectrum potency resistance development stability mechanism of action and novelty of structure Leads that emerge will be tested in mouse models of infection The end result of Phase II will be three lead compounds showing efficacy in animal models This will enable subsequent preclinical development towards an IND clinical studies and FDA approval of a new therapeutic We believe this strategy advancing leads while backing them with a discovery pipeline greatly increases the chances for the projectandapos s success PUBLIC HEALTH RELEVANCE The overall goal of the project is to use our innovative technologies to discover new antibacterial compounds Multi drug resistant bacterial pathogens are on the rise and have become a major public health problem The continuing addition of new antibacterial compounds without cross resistance to current antibiotics is the only way to effectively manage the crisis


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 219.07K | Year: 2015

DESCRIPTION provided by applicant The slow pace of antibiotic discovery is being outmatched by rapid acquisition of resistance by our pathogens The need is especially acute in the case of Mycobacterium tuberculosis TB where strains of XDR TB resistant to the majority of standard therapeutics are rapidly spreading In a previous RO screen development project we collaborated with Professor Kim Lewis Northeastern University to establish a drug discovery platform for identifying compounds specifically acting against TB The platform is based on two innovations the use of uncultured bacteria as an untapped source of secondary metabolites and a species specific screen Uncultured bacteria represent of all species and we access them by cultivation in their natural environment the soil in a specialized diffusion chamber Our findings show that this is an excellent source of novel antimicrobials However even with this previously inaccessible resource most of the effort is wasted on rediscovering known compounds We reasoned that the background can be eliminated if discovery is focused on a species specific compound Natural compounds specifically acting against TB are essentially unknown so a screen for specific anti TB compounds will produce hits that will have a high probability of being novel substances A TB specific compound will likely not hit a target present in humans and will not harm the human microbiome We performed a pilot screen against TB and a counter screen against Staphylococcus aureus The screen produced a hit rate of for TB specific extracts One of the extracts from a rare Actinomycete contained a novel antimicrobial with excellent activity against TB high specificity for mycobacteria and no cytotoxicity This compound which we named lassomycin killed both growing and dormant cells of TB better than the best current killing agent rifampicin Whole genome sequencing of lassomycin resistant mutants showed that it targets the C subunit of the essential mycobacterial ClpP P C Lassomycin inhibits this protease and activates the ATPase of ClpC This dual action is responsible for the excellent killing Lassomycin serves as proof of principle for this platform In the proposed project the PI Losee Ling VP of Biology at NovoBiotic will continue collaborating with Dr Kim Lewis to perform a large scale screen of extracts from uncultured bacteria for TB specific compounds The compounds will be isolated structurally characterized and tested against a panel of gut symbionts to establish novelty and specificity The principal mode of action will be identified by whole genome sequencing of resistant mutants The result of the project will be eight validated leads providing a solid basis for a subsequent Phase II effort aimed at drug development PUBLIC HEALTH RELEVANCE Tuberculosis remains a leading health crisis with one third of the worldandapos s population infected and antibiotic resistance a growing problem Discovery of novel compounds acting specifically against Mycobacterium tuberculosis will enable the development of new anti TB therapies


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 224.36K | Year: 2015

DESCRIPTION provided by applicant The overall goal of this project is to discover novel antibiotics to combat important drug resistant pathogens One effective countermeasure against such pathogens is novel antibiotics but the rate of antibiotic discovery has been in steady decline All the more recently introduced antibiotics are derivatives of older antibiotics or resulted from revival of initially discarded compounds which were discovered decades ago such as daptomycin linezolid synercid and fidaxomycin Clinically used antibiotics have traditionally been discovered by screening for active secondary metabolites of readily culturable microorganisms This resource represents andlt of all microbial diversity in nature The other andgt unexplored and previously unavailable microorganisms are arguably the single most promising resource for novel antibiotics NovoBiotic directly addresses the bottleneck of antibiotic discovery by using unique cultivation approaches the diffusion chamber and trap methodologies to isolate previously andquot uncultivableandquot microorganisms This approach has resulted in new compounds so far at a rate far higher than the predicted industry standard Several of these compounds are of principal novelty and are in development including Novo a DNA G quadruplex binder currently in development as an anti cancer agent in collaboration with the National Cancer Institute Novo a macrolactam inhibitor of cell wall biosynthesis lassomycin an inhibitor of the essential ClpP P C protease of M tuberculosis and teixobactin a novel cell wall synthesis inhibitor This project takes the next step and extends the technology to shallow water marine invertebrate microbe symbioses ubiquitously present and easily accessible in local communities From the limited exploration conducted to date a number of bioactive compounds with unique properties have been discovered from marine symbioses including anti tumor and anti microbial compounds There is strong evidence that it is the associated microorganisms living in association with the host invertebrates that produce the bioactive compounds We will develop our methods to isolate novel microbial species living in association with marine invertebrates and screen these strains for antimicrobial activity We will compare the diversity and novelty of active compounds from strains isolated from the diffusion chamber trap and conventional plating The end result of this Phase I project will be proof of concept of new technologies to discover antibiotics from a poorly explored source of microbial diversity formerly andquot uncultivableandquot microbial species from marine invertebrate microbe symbioses PUBLIC HEALTH RELEVANCE It is widely recognized that new antibiotics are needed to combat drug resistant bacterial infections The proposed study will exploit the previously inaccessible microbial diversity of marine invertebrate symbionts to discover novel antibiotics


Grant
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 1.49M | Year: 2015

DESCRIPTION provided by applicant The long term goal of this program is to develop a novel antimicrobial teixobactin into a therapeutic for treating a wide range of infections caused by Gram positive pathogens The goal of this Phase II project is to perform preclinical development of teixobactin to enable subsequent IND studies NovoBiotic has been exploiting uncultured bacteria that make up of all microorganisms for production of secondary metabolites Initial growth of microorganisms in a diffusion chamber in their natural environment enables subsequent cultivation in vitro Teixobactin is an unusual depsipeptide that contains enduracididine methyl phenylalanine and D amino acids and is the first member of a novel class of peptidoglycan synthesis inhibitors We saw no resistance development to this compound Teixobactin targets lipid II precursor of peptidoglycan and lipid III precursor of teichoic acid It binds to undecaprenyl PP sugars which are not known to be modified as opposed to a later lipid II D Ala D Ala modifiable form the target of vancomycin This unique mode of action binding to two essential targets neither of which is a protein explains the lack of resistance development Teixobactin has potent activity against a broad range of Gram positive bacteria Staphylococcus aureus Streptococcus pneumoniae Bacillus anthracis Mycobacterium tuberculosis Enterococcus faecalis and E faecium It is active against resistant forms of these pathogens including methicillin resistant S aureus MRSA and vancomycin resistant enterococci Teixobactin was highly efficacious in a murine MRSA septicemia and thigh infection models and against S pneumoniae in a lung infection model In this project we will complete key non GLP studies of teixobactin A set of in vitro and in vivo studies will be performed including expanded microbiological testing toxicity pharmacokinetic studies and in vivo efficacy The simplest clinical indication for teixobactin is acute bacterial skin and skin structure infections ABSSSI due to its high potency against key pathogens causing this disease well defined path to approval and a large patient population We will also test the compound in animal models of hospital acquired or ventilator associated bacterial pneumonia HABP VABP and enterococcal endocarditis where there are often no reliable options for treatment Production optimization will increase the yield of the compound for supporting product development The results of this project will produce a therapeutic lead candidate ready to enter IND studies PUBLIC HEALTH RELEVANCE It is widely recognized that new antibiotics are needed to combat drug resistant bacterial infections The proposed study will address this need by the preclinical development of a novel antibiotic to treat serious conditions such as skin and skin structure infections hospital acquired pneumonia and enterococcal endocarditis

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