Preclinical development of teixobactin, a new antibiotic

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