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.
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.
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
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.
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