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 99% 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 4-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 Statement: 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.
Project Terms: Acute; Address; Amino Acids; animal efficacy; Animal Model; Antibiotics; antimicrobial; Antineoplastic Agents; Bacillus anthracis; Bacteria; Bacterial Infections; Bacterial Pneumonia; base; Binding (Molecular Function); Biodistribution; Cell Wall; Clinical; Clostridium difficile; Collaborations; combat; Depsipeptides; Development; Diffusion; Disease; Dose; drug development; Drug Kinetics; Drug resistance; Endocarditis; Enterococcus faecalis; Environment; Evaluation; Exposure to; Fermentation; G-Quartets; Goals; Gram-Positive Bacteria; Half-Life; Hospitals; Human; improved; In Vitro; in vivo; Infection; inhibitor/antagonist; Killings; Lead; Lipid III; Lipids; Liver; Lung; member; Metabolic; methicillin resistant Staphylococcus aureus (organism); microorganism; microorganism growth; Modeling; mouse model; muramyl-NAc-(pentapeptide)pyrophosphoryl-undecaprenol; Mus; mycobacterial; Mycobacterium tuberculosis; National Cancer Institute; Nosocomial pneumonia; novel; pathogen; patient population; Peptide Hydrolases; Peptidoglycan; Pharmaceutical Preparations; Phase; phenylalanine methyl ester; pre-clinical; Preparation; product development; Production; programs; Property; Proteins; public health relevance; Rattus; Regimen; Resistance; Resistance development; Rodent Model; Septicemia; Skin; Soil; Staphylococcus aureus; Streptococcus pneumoniae; Streptococcus pyogenes; Structure; sugar; Teichoic Acids; Testing; Therapeutic; Thigh structure; Time; Tissues; Toxic effect; Toxicity Tests; undecaprenyl pyrophosphate; Vancomycin; Vancomycin resistant enterococcus; Ventilator
