Phase II year
2020
(last award dollars: 2021)
Phase II Amount
$2,989,150
The goal of this project is to continue developing teixobactin (TXB) as an antibiotic to combat weaponized anthrax. This work will be done in parallel to an ongoing preclinical development program, which is advancing TXB for treating infections caused by other serious pathogens such as methicillin resistant Staphylococcus aureus (MRSA). TXB has shown excellent efficacy in several animal models of infection, including a rabbit model of inhalation anthrax recently run at the University of Texas Medical Branch (Galveston, TX). Due to TXBs unusual mechanism of action binding two different bacterial cell wall targets, neither of which is a protein TXB represents an example of a compound that is exceptionally free of resistance development and thus is an excellent candidate as a countermeasure for anthrax. The work in this grant will include the following Specific Aims: Aim 1 will provide at least 50 grams of non-cGMP teixobactin to fulfill all studies in the proposal. In addition, at least 200 grams of cGMP material will be produced at a contract manufacturer for planned future studies. Aim 2 will focus on the following studies to further understand TXBs in vitro properties: (a) MIC testing against a panel of key B. anthracis isolates, including isolates resistant to current anthrax drugs; (b) determine B. anthracis resistance frequency to teixobactin; and (c) protein binding studies using rabbit, nonhuman primate (NHP), and human serum to determine free drug levels. Aim 3 will determine the minimal therapeutic TXB dose in the rabbit anthrax efficacy model, with associated pharmacokinetic (PK) profiling and histopathology. The information in Aim 3, in addition to the toxicology, safety and PK/PD studies being run in parallel with this project, will help inform NHP and human dosing. At the conclusion of this grant, TXB will be prepared to enter a GLP-compliant, NHP inhalation anthrax study and a Phase I clinical study, all in support of FDA approval for treating anthrax under the Animal Rule.
Public Health Relevance Statement: NARRATIVE Weaponized anthrax using drug-resistant Bacillus anthracis is a serious biothreat. The focus of this project is to advance our newly discovered antibiotic teixobactin as a countermeasure for anthrax infections.
Project Terms: Acute; animal efficacy; Animal Model; animal rule; Animals; Anthrax disease; Antibiotic Therapy; Antibiotics; Bacillus anthracis; Binding; Binding Proteins; Bioreactors; biothreat; Cell Count; Cell Wall; Cells; Clinical; Clinical Research; Clinical Trials; combat; Contracts; Cyclic GMP; Development; Dose; Drug Kinetics; Drug resistance; drug resistant pathogen; Drug usage; efficacy study; Engineering; Evaluation; Exposure to; Fermentation; Funding; Future; Goals; Gram-Positive Bacteria; Grant; Histopathology; Human; In Vitro; Infection; Inhalation; Length; Lipid III; Lipids; Lung; Manufacturer Name; Medical; methicillin resistant Staphylococcus aureus; Methods; microbial; Modeling; Monkeys; mutant; Mycobacterium tuberculosis; nonhuman primate; Onset of illness; Organ; Oryctolagus cuniculus; pathogen; Pathogenicity; Peptidoglycan; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Plasma; Plasma Proteins; Pneumococcal Infections; preclinical development; Preparation; Production; Program Development; Property; Proteins; Resistance; Resistance development; resistance frequency; Running; Safety; Sampling; scale up; Septicemia; Serum; side effect; Skin; Source; Staphylococcus aureus; Structure; Teichoic Acids; Testing; Texas; Therapeutic; therapy development; therapy resistant; Tissues; Toxicology; Universities; weapons; Work
