Non-Tuberculosis Mycobacteria (NTM) are responsible for widespread, life threatening infections of the lungs, skin, lymphatic and hematological systems. The rapid, global spread of resistant organisms has significantly reduced the number of agents that can be used effectively to treat these infections. Of specific clinical relevance are the slow-growing Mycobacterium avium complex (MAC) comprised of M. avium, M. intracellulare and M. chimaera. MACs are widely distributed throughout the environment, often found in soil, water and airborne particulates. Mycobacterial infections are a growing cause of concern in immunocompromised individuals with underlying comorbidities and represent a significant threat as opportunistic pathogens. Over the past three decades, the incidence of infections caused by MAC NTMs have increased more than 30-fold. Change in the world climate is allowing these once-unknown environmental mycobacteria to flourish and establish themselves as an increasingly common source of deadly infections, accounting for approximately 40% of the pulmonary infections (NTM lung disease) found in immunocompromised patients. Currently in the United States, the prevalence of MAC NTM infections is approximately 50 per 100,000 population, equating to more than 200,000 new cases annually. It is estimated that this number will grow at a rate of +8% per year. The costs associated with treatment of NTM-related infections exceeded $800M in 2018. MAC NTM-LD represents an unmet clinical need as there are few safe and effective drugs available to combat the infections they cause. Furthermore, because standard antibiotics have so much environmental exposure, many MAC isolates are natively drug resistant. QMD is focused on the development of an inhaled therapeutic that inhibits the essential NTM enzyme dihydrofolate reductase (DHFR), which is involved in the biosynthesis of the nucleic acid building blocks that are a key player in the folate cycle and a validated antibiotic drug target.
Public Health Relevance Statement: Public Health Relevance: Mycobacterium avium complex (MAC), a subset of non-tuberculosis mycobacteria (NTM), are responsible for more than 200,000 life threatening pulmonary infections (NTM Lung disease or NTM-LD) each year, particularly in immunocompromised patients. The goal of this grant is to develop a new antifolate as an inhaled alternative for the treatment of NTM-LD infections.
Project Terms: in vitro activity; preclinical evaluation; pre-clinical evaluation; product development; candidate selection; non-tuberculosis mycobacteria; non-tuberculosis mycobacterial; non-tuberculous mycobacteria; non-tuberculous mycobacterial; nontuberculosis mycobacterial; nontuberculous mycobacteria; nontuberculous mycobacterial; Drug Targeting; Formulation; nanomolar; nano-molar; healthcare community; health care community; efficacy study; Inhalation; Inhaling; lead candidate; in vivo evaluation; in vivo testing; Lung infections; pulmonary infections; opportunistic pathogen; Accounting; Animals; Antibiotics; Antibiotic Agents; Antibiotic Drugs; Miscellaneous Antibiotic; Chimera organism; Chimera; Climate; Meteorological Climate; climatic; comorbidity; co-morbid; co-morbidity; Drug resistance; drug resistant; resistance to Drug; resistant to Drug; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Environment; Environmental Exposure; Enzymes; Enzyme Gene; Folic Acid; Folate; Pteroylglutamic Acid; Vitamin M; vitamin Bc; Folic Acid Antagonists; Antifolates; Folate Analog; Folate Inhibitors; Folic Acid Analog; Folic Acid Inhibitors; folate antagonist; Goals; Grant; Growth; Generalized Growth; Tissue Growth; ontogeny; Hematology; Human; Modern Man; In Vitro; Incidence; Infection; Lead; Pb element; heavy metal Pb; heavy metal lead; Libraries; Liposomes; Liposomal; Lung; Lung Respiratory System; pulmonary; Lung diseases; Pulmonary Diseases; Pulmonary Disorder; disease of the lung; disorder of the lung; lung disorder; Multienzyme Complexes; enzyme complex; Genus Mycobacterium; Mycobacterium; Mycobacterium avium; M avium; M. avium; Mycobacterium avium Complex; M avium Complex; M. avium Complex; M. avium intracellulare; MAIC; Mycobacterium avium-intracellulare; Mycobacterium avium-intracellulare Complex; Mycobacterium avium-intracellulare Infection; Mycobacterium Avium Infection; Mycobacterium intracellulare Infection; Mycobacterium Infections; Mycobacterial Infection; living system; Organism; Permeability; Program Development; Airway infections; Respiratory Infections; Respiratory Tract Infections; Safety; cutaneous infection; infected skin; skin infection; Infectious Skin Diseases; Soil; Dihydrofolate Dehydrogenase; Folic Acid Reductase; Tetrahydrofolate Dehydrogenase; Dihydrofolate Reductase; United States; Water; Hydrogen Oxide; Work; Clarithromycin; 6-O-Methylerythromycin; 6-O-methyl-erythromycin; Biaxin; Immunocompromised Host; Immunocompromised; Immunocompromised Patient; Immunosuppressed Host; immunosuppressed patient; Mycobacterium intracellulare; Battey Bacillus; M intracellulare; M. intracellulare; Treatment Cost; Clinical; Phase; Evaluation; Individual; Therapeutic; Knowledge; Life; Source; Route; System; mycobacterial; nucleic acid biosynthesis; physical property; Isoforms; Protein Isoforms; aqueous; Position; Positioning Attribute; Modeling; Dose; Absorption, Distribution, Metabolism, and Excretion Study; ADME Study; airborne particulate; Airborne Particulate Matter; in vitro Model; in vivo; in vivo Model; Collection; New Agents; Small Business Technology Transfer Research; STTR; trend; Preparation; Lymphatic; Development; developmental; safety study; cost; efficacy evaluation; efficacy analysis; efficacy assessment; efficacy examination; evaluate efficacy; examine efficacy; Resistance profile; Resistant profile; pathogen; Population; Prevalence; Resistance; resistant; clinically relevant; clinical relevance; therapeutic development; therapeutic agent development; combat; public health relevance; alternative treatment; standard of care
