Document text
Principal Investigator: Dallas Hughes
Organization: NOVOBIOTIC PHARMACEUTICALS, LLC
Fiscal Year: 2024
Award: $992,480
Funding agency: National Institute of Allergy and Infectious Diseases
ABSTRACT
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.
Terms: <AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Acute><Agreement><Animal Model><Animal Models and Related Studies><Animals><Anthrax><Anthrax disease><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Antibiotics against tuberculosis><Antitubercular Antibiotics><Antitubercular Drugs><Bacteremia><Binding><Blood><Blood Plasma><Blood Reticuloendothelial System><C3HeB/FeJ Mouse><CAT scan><COVID-19><CT X Ray><CT Xray><CT imaging><CT scan><CV-19><Cause of Death><Cell Wall><Cell membrane><Chronic><Code><Coding System><Collaborations><Computed Tomography><Coronavirus Infectious Disease 2019><Cytoplasmic Membrane><D pneumoniae><D. pneumoniae><DNA><Deoxyribonucleic Acid><Development><Development Plans><Diplococcus pneumoniae><Disease><Disorder><Domestic Rabbit><Dose><Drug Combinations><Drug Exposure><Drug Kinetics><Drug Resistance Tuberculosis><Drug Resistant TB><Drug Resistant Tuberculosis><Drug resistance><Drug resistance in tuberculosis><Drugs><Epithelium><Exhibits><Fermentation><Goals><Gram-Positive Bacteria><HIV><Human><Human Immunodeficiency Viruses><In Vitro><Infection><Infectious Agent><Infectious Skin Diseases><Inhalation Therapy><Intranasal Administration><Intranasal Drug Administration><Intravenous><Investigational Drugs><Investigational New Drugs><Isonicotinic Acid Hydrazide><LAV-HTLV-III><Lesion><Linezolid><Lipid III><Lipids><Liquid substance><Lung><Lung Granuloma><Lung Respiratory System><Lung TB><Lung Tuberculosis><Lymphadenopathy-Associated Virus><M tb><M tuberculosis><M tuberculosis infection><M. tb><M. tb infection><M. tuberculosis><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MDR Tuberculosis><MDR-TB><MPPPUP><MRSA><MTB infection><Macromolecular Structure><Medication><Membrane><Methicillin Resistant S. Aureus><Mice><Mice Mammals><Miscellaneous Antibiotic><Modeling><Modern Man><Molecular Interaction><Molecular Structure><Multi-Drug Resistance><Multi-Drug Resistant Tuberculosis><MultiDrug Resistance Tuberculosis><Multidrug Resistance><Multidrug-Resistant Tuberculosis><Multiple Drug Resistance><Multiple Drug Resistant><Murine><Mus><Mycobacterium tuberculosis><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><Necrosis><Necrotic><Non-adherent patient><Nonadherent patient><Oral><Oral Tuberculosis><Oryctolagus cuniculus><Patient Non Compliance><Patient Non-Adherence><Patient Nonadherence><Patient Noncompliance><Patients><Persons><Pharmaceutical Preparations><Pharmacokinetics><Phase><Plasma><Plasma Membrane><Plasma Serum><Pneumococcus><Pneumonia><Pre IND FDA meeting><Pre-IND mtg><Primary Infection><Production><Property><Pulmonary Pathology><Pulmonary TB><Pulmonary Tuberculosis><Pyrazinamide><Pyrazinecarboxamide><Rabbits><Rabbits Mammals><Regimen><Relapse><Resistance><Resistance development><Resistance to Multi-drug><Resistance to Multidrug><Resistance to Multiple Drug><Resistant development><Resistant to Multiple Drug><Resistant to multi-drug><Resistant to multidrug><Reticuloendothelial System, Serum, Plasma><Route><S pneumoniae><S. pneumoniae><Site><Skin><Streptococcus pneumoniae><Structure><TB antibiotics><TB drug resistance><TB drugs><TB infection><TB therapy><TB treatment><Teichoic Acids><Testing><Time><Tomodensitometry><Toxic effect><Toxicities><Treatment Period><Tuberculosis><Tuberculosis antibiotics><Universities><Virus-HIV><X-Ray CAT Scan><X-Ray Computed Tomography><X-Ray Computerized Tomography><Xray CAT scan><Xray Computed Tomography><Xray computerized tomography><Zyvox><anti-TB drugs><anti-tuberculosis drugs><antibiotic against TB><arm><bacteraemia><bacterial sepsis><bactericidal><bactericide><catscan><cell killing><comparable efficacy><comparative efficacy><compare efficacy><computed axial tomography><computer tomography><computerized axial tomography><computerized tomography><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><cutaneous infection><developing resistance><developmental><disseminated TB><disseminated tuberculosis><drug resistance in TB><drug resistant><drug resistant in tuberculosis><drug/agent><efficacy study><efficacy testing><extensive drug resistance><extensively drug resistant><extreme drug resistance><fluid><global health><high risk><infected skin><infection due to Mycobacterium tuberculosis><infectious organism><isoniazid><liquid><lung lesion><lung pathology><membrane structure><methicillin resistance Staphylococcus aureus><methicillin resistant Staphylococcus aureus><methicillin resistant strains of Staphylococcus aureus><microbial><model of animal><mouse model><mtb><multi-drug resistant><multidrug resistant><multidrug use><multidrug-resistant TB><multiple drug use><muramyl-NAc-(pentapeptide)pyrophosphoryl-undecaprenol><murine model><mutant><new antibiotic class><new antibiotic type><non-compliance><non-compliant><non-contrast CT><non-invasive monitor><noncompliance><noncompliant><noncontrast CT><noncontrast computed tomography><noninvasive monitor><novel antibiotic class><oral TB><pathogen><peptidoglycan precursor lipid II><plasmalemma><pneumonia model><pneumonia models><poly drug use><polydrug use><pre-IND consultation><pre-IND discussion><pre-IND meeting><pre-Investigational New Drug meeting><pre-clinical development><preclinical development><pulmonary><pulmonary granuloma><pulmonary lesion><resistance strain><resistance to Drug><resistant><resistant strain><resistant to Drug><side effect><skin infection><synergism><treat M. tuberculosis><treat Mtb><treat Mycobacterium tuberculosis><treat tb><treat tuberculosis><treatment days><treatment duration><tuberculosis drugs><tuberculosis infection><tuberculosis therapy><tuberculosis treatment><tuberculous spondyloarthropathy>