The goal of this proposal is to investigate the potential for teixobactin (TXB) to treat drug-resistant tuberculosis (TB). TB is a major global health issue and second largest killer by an infectious agent. Non-compliance by TB patients due to lengthy treatment times have resulted in drug-resistant strains that require longer treatment durations and a high risk of adverse side effects. Thus, there is a pressing need for a drug regimen that is safer, shorter in duration and avoids drug resistance. The most remarkable property of TXB is the lack of any detectable resistance. This lack of resistance is most likely due to its two-pronged mode of action. TXB hits two related targets-lipid II, precursor of peptidoglycan and lipid III, precursor of wall teichoic acid. These highly conserved targets are not mutable, as they are not proteins and are not directly coded by DNA. In addition, once bound to its bacterial target, TXB self-associates into large macromolecular structures that weaken the membrane and further contribute to its potent killing activity. Likely, these structures are irreversible, which can explain how low TXB doses are so effective in various animal models of infection. Since discovering TXB, we and others have failed to generate resistant mutants in any species including Mycobacterium tuberculosis. Importantly, in a recent study conducted at John Hopkins University, TXB was highly efficacious in a validated rabbit model of TB, demonstrating its promise to treat this devastating disease. TXB is in preclinical development as an intravenous (IV) drug for treating serious skin infections caused by pathogens such as MRSA. At a pre-Investigational New Drug (IND) meeting, the FDA generally agreed with our development plan, and an IND submission is planned in approximately 1.5 to 2 years. The goal of this proposal is to continue exploring TXB's potential to treat TB. In this project, Aim 1 will produce enough TXB for all the proposed studies. Aim 2 will conduct blood and lung PK studies in mice using intranasal administration of TXB. Intranasal administration offers several advantages, including delivering the drug directly to the primary site of infection (lung) and avoiding side effects with drugs delivered systemically. Aim 3 will use the Kramnik TB mouse model to test the efficacy of intranasal TXB delivered alone and in combination with current TB drugs. Kramnik mice develop pulmonary granulomas that more closely resembled human lesions. Aim 4 will use a validated rabbit model to compare the efficacy of IV-delivered TXB alone and in combination with other TB drugs. In Aims 3 and 4, TXB drug regimens will be compared to the BPaL (bedaquiline, pretomanid, linezolid) regimen currently used for multidrug resistant TB. With successful completion of these studies, we will have demonstrated the promise of TXB for treating drug-resistant TB and explored a convenient route of administration.
Public Health Relevance Statement: Narrative Tuberculosis continues to be a leading cause of death worldwide and the second leading infectious killer after Covid-19. In 2020, an estimated 10 million people became ill and 1.5 million died (including 214,000 co-infected with HIV) from tuberculosis. The purpose of this project is to develop the new antibiotic, teixobactin, to treat tuberculosis.
Project Terms: Intranasal Administration; Intranasal Drug Administration; Animals; Anthrax disease; Anthrax; Antibiotics; Antibiotic Agents; Antibiotic Drugs; Miscellaneous Antibiotic; Antitubercular Antibiotics; Antibiotics against tuberculosis; Tuberculosis antibiotics; Bacteremia; bacteraemia; bacterial sepsis; Blood; Blood Reticuloendothelial System; Cause of Death; Cell membrane; Cytoplasmic Membrane; Plasma Membrane; plasmalemma; Cell Wall; Disease; Disorder; DNA; Deoxyribonucleic Acid; Drug Combinations; Drug resistance; drug resistant; resistance to Drug; resistant to Drug; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Investigational Drugs; Investigational New Drugs; Exhibits; Fermentation; Goals; Gram-Positive Bacteria; Human; Modern Man; In Vitro; Infection; Inhalation Therapy; isoniazid; Isonicotinic Acid Hydrazide; Lipids; Lung; Lung Respiratory System; pulmonary; Molecular Structure; Macromolecular Structure; Mus; Mice; Mice Mammals; Murine; Mycobacterium tuberculosis; M tb; M tuberculosis; M. tb; M. tuberculosis; mtb; Persons; Necrotic; Necrosis; Patients; Murein; Peptidoglycan; Pharmacokinetics; Drug Kinetics; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Plasma; Pneumonia; Production; Pyrazinecarboxamide; Pyrazinamide; Domestic Rabbit; Rabbits; Rabbits Mammals; Oryctolagus cuniculus; Relapse; cutaneous infection; infected skin; skin infection; Infectious Skin Diseases; D pneumoniae; D. pneumoniae; Diplococcus pneumoniae; Pneumococcus; S pneumoniae; S. pneumoniae; Streptococcus pneumoniae; Teichoic Acids; Testing; Time; X-Ray Computed Tomography; CAT scan; CT X Ray; CT Xray; CT imaging; CT scan; Computed Tomography; Tomodensitometry; X-Ray CAT Scan; X-Ray Computerized Tomography; Xray CAT scan; Xray Computed Tomography; Xray computerized tomography; catscan; computed axial tomography; computer tomography; computerized axial tomography; computerized tomography; non-contrast CT; noncontrast CT; noncontrast computed tomography; Tuberculosis; M tuberculosis infection; M. tb infection; M. tuberculosis infection; M.tb infection; M.tuberculosis infection; MTB infection; Mycobacterium tuberculosis (MTB) infection; Mycobacterium tuberculosis infection; TB infection; disseminated TB; disseminated tuberculosis; infection due to Mycobacterium tuberculosis; tuberculosis infection; tuberculous spondyloarthropathy; Oral Tuberculosis; Pulmonary Tuberculosis; Lung TB; Lung Tuberculosis; Pulmonary TB; Universities; Site; Acute; Chronic; Phase; Multidrug-Resistant Tuberculosis; MDR Tuberculosis; MDR-TB; Multi-Drug Resistant Tuberculosis; MultiDrug Resistance Tuberculosis; multidrug-resistant TB; Lesion; Epithelial; Lung Granuloma; pulmonary granuloma; Development Plans; Multidrug Resistance; Multiple Drug Resistance; Multiple Drug Resistant; Resistance to Multi-drug; Resistance to Multidrug; Resistance to Multiple Drug; Resistant to Multiple Drug; Resistant to multi-drug; Resistant to multidrug; multi-drug resistant; multidrug resistant; Multi-Drug Resistance; Collaborations; fluid; liquid; Liquid substance; infectious organism; Infectious Agent; Intravenous; Non-adherent patient; Nonadherent patient; Patient Non Compliance; Patient Non-Adherence; Patient Nonadherence; Patient Noncompliance; Oral; Treatment Period; treatment days; treatment duration; Route; non-compliant; noncompliance; noncompliant; non-compliance; meetings; membrane structure; Membrane; mutant; cell killing; synergism; Animal Models and Related Studies; model of animal; model organism; Animal Model; microbial; Toxicities; Toxic effect; Lipid III; Zyvox; Linezolid; multidrug use; poly drug use; polydrug use; multiple drug use; Structure; Drug Exposure; lung pathology; Pulmonary Pathology; Coding System; Code; Modeling; Property; Skin; Molecular Interaction; Binding; MRSA; Methicillin Resistant S Aureus; Methicillin Resistant S. Aureus; methicillin-resistant S. aureus; methicillin resistant Staphylococcus aureus; Dose; global health; C3HeB/FeJ Mouse; Development; developmental; bactericide; bactericidal; Drug resistance in tuberculosis; Drug Resistance Tuberculosis; Drug Resistant TB; Drug Resistant Tuberculosis; TB drug resistance; drug resistant in tuberculosis; Resistance development; Resistant development; developing resistance; pathogen; Resistance; resistant; mouse model; murine model; non-invasive monitor; noninvasive monitor; tuberculosis drugs; Antitubercular Drugs; TB drugs; anti-TB drugs; anti-tuberculosis drugs; antituberculosis drugs; high risk; resistant strain; resistance strain; efficacy testing; comparative efficacy; compare efficacy; Regimen; arm; extensive drug resistance; extensively drug resistant; extreme drug resistance; HIV/TB; HIV/Mtb; HIV/mycobacterium tuberculosis; HIV/tuberculosis; M. tuberculosis/HIV; Primary Infection; efficacy study; preclinical development; pre-clinical development; pneumonia model; pneumonia models; side effect; COVID-19; COVID19; CV-19; CV19; corona virus disease 2019; coronavirus disease 2019; coronavirus disease-19; coronavirus infectious disease-19; novel antibiotic class; new antibiotic class; new antibiotic type; lung lesion; pulmonary lesion
