Tuberculosis (TB), caused by infection with the bacterium Mycobacterium tuberculosis (Mtb), is a leading cause of mortality due to infection, globally. In 2020, 10 million people were newly diagnosed with TB and 1.5 million people died from the disease. As efforts to treat TB expand, the prevalence of infections caused by drug-resistant Mtb strains (DR-TB) that are resistant to one or more frontline standard of care (SoC) antibiotics is increasing, in part due to the long duration (6 months) of combination therapy (4 antibiotics) for drug-sensitive TB (DS-TB), which leads to poor patient adherence. Treatment for DR-TB is even longer, ranging from 6-24 months typically, with 3, 4 or more antibiotics taken in combination. While the last decade has seen a TB drug development "renaissance," including the discovery of bedaquiline, newly approved regimens still suffer from serious side effects and can be cost prohibitive. Therefore, new classes of drugs with new MoAs that can be combined with existing or new TB drugs in the pipeline are desperately needed. The success of bedaquiline, which disrupts energy metabolism in Mtb and has shown promise in reducing treatment times for DR-TB, has accompanied an explosion of drug discovery targeting respiration in Mtb. In this application, Fimbrion proposes to develop a thiazolino-pyridone (TZP) small molecule series with growth inhibitory activity against Mtb as a novel drug for treating TB. While the target of this compound series is currently unknown, TZPs appear to act through disruption of Mtb respiration. Interestingly, current TZPs not only have direct antimycobacterial activity, but they can also potentiate the activity of isoniazid (INH), an important frontline TB antibiotic, even restoring INH activity against INH-resistant Mtb in vitro. Our primary goal in this project is to develop a first-in-class, orally bioavailable, antimycobacterial TZP compound that could become part of a new frontline TB drug regimen to help shorten the duration of treatment. Currently, our most potent TZP compounds have sub-micromolar growth inhibition potency in vitro, and favorable drug-like properties. Therefore, our primary Phase I goal will be to improve growth inhibition potency while maintaining and/or improving the drug-like properties of the lead compounds to enable testing of optimized compounds in an animal model of Mtb infection. Specifically, we will 1) use medicinal chemistry drug design strategies to improve in vitro potency, metabolic stability, and solubility, and will establish in vivo pharmacokinetic (PK) profiles (including oral bioavailability) for optimized TZPs in mice; and 2) investigate the in vitro and in vivo efficacy of prioritized lead TZPs and generate spontaneous mutants resistant to these compounds to better understand the bacterial target and MoA. As we have found that the antimycobacterial potency of our TZPs tracks with their ability to potentiate INH, we will continue to spot-check this secondary property throughout the optimization of our TZPs. Upon completion of this project, we expect to identify an advanced lead TZP compound with demonstrated efficacy in a mouse model of acute TB, which could be further developed in a future Phase II SBIR project as part of a combination therapy for treating both DS- and DR-TB.
Public Health Relevance Statement: Project narrative: Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis (Mtb), is a leading cause of human mortality in the world for a single infectious agent and drug-resistance to standard of care frontline and even second-line antibiotics is increasing, highlighting the need for new therapies. In this application, we propose to develop a series of small molecule compounds for the treatment of TB, resulting in the selection of optimized drug candidates. The proposed studies have the potential to result in the development of a new family of anti- mycobacterials to be used to treat both drug-sensitive and drug-resistant TB.
Project Terms: Agar; Antibiotic Agents; Antibiotic Drugs; Miscellaneous Antibiotic; Antibiotics; Antibiotics against tuberculosis; TB antibiotics; Tuberculosis antibiotics; antibiotic against TB; Antitubercular Antibiotics; Bacteria; Biological Availability; Bioavailability; Physiologic Availability; Cell Line; CellLine; Strains Cell Lines; cultured cell line; Cells; Cell Body; Pharmaceutical Chemistry; Medicinal Chemistry; Pharmaceutic Chemistry; Combined Modality Therapy; Multimodal Therapy; Multimodal Treatment; combination therapy; combined modality treatment; combined treatment; multi-modal therapy; multi-modal treatment; Disease; Disorder; Drug Design; Drug resistance; drug resistant; resistance to Drug; resistant to Drug; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Energy Metabolism; Energy Expenditure; Explosion; Family; Future; Goals; Growth; Generalized Growth; Tissue Growth; ontogeny; Half-Life; In Vitro; indexing; Infection; isoniazid; Isonicotinic Acid Hydrazide; Lead; Pb element; heavy metal Pb; heavy metal lead; Libraries; Marketing; Liver Microsomes; Mission; monocyte; Blood monocyte; Marrow monocyte; mortality; Mus; Mice; Mice Mammals; Murine; Mutation; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Mycobacterium tuberculosis; M tb; M tuberculosis; M. tb; M. tuberculosis; mtb; Persons; Patients; Drug Kinetics; Pharmacokinetics; Pharmacology; Plasma; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Production; Pyridones; Pyridinones; Respiration; respiratory mechanism; Risk; Safety; Solubility; Structure-Activity Relationship; chemical structure function; structure function relationship; Testing; 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; Renaissance; Generations; Resistance to antibiotics; Resistant to antibiotics; antibiotic drug resistance; antibiotic resistant; Antibiotic Resistance; Respiratory Chain; dosage; human mortality; improved; Acute; Phase; Series; Hypoxic; Oxygen Deficiency; Hypoxia; Licensing; analog; Antibacterial Agents; anti-bacterial; antibacterial; Anti-Bacterial Agents; Intellectual Property; Therapeutic; Metabolic; Spottings; Infectious Agent; infectious organism; scaffold; scaffolding; Antimycobacterial Agents; Anti Mycobacterial Agents; antimycobacterial; Oral; treatment duration; Treatment Period; treatment days; meter; interest; cytotoxicity; Lytotoxicity; mutant; success; functional group; Animal Model; Animal Models and Related Studies; model of animal; aqueous; Toxic effect; Toxicities; novel; Modeling; Property; drug development; drug discovery; Drops; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; pharmaceutical; Pharmacologic Substance; Patient Compliance; patient adherence; patient cooperation; therapy compliance; therapy cooperation; treatment compliance; compliance behavior; small molecule; Antimicrobial Resistance; Antimicrobial resistant; Resistance to antimicrobial; anti-microbial resistance; anti-microbial resistant; resistance to anti-microbial; resistant to anti-microbial; resistant to antimicrobial; Aerobic; in vivo; Newly Diagnosed; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Process; Development; developmental; pre-clinical; preclinical; bactericide; bactericidal; cost; Drug Resistance Tuberculosis; Drug Resistant TB; Drug Resistant Tuberculosis; TB drug resistance; drug resistance in TB; drug resistant in tuberculosis; Drug resistance in tuberculosis; Outcome; INH resistance; INH resistant; Isoniazid resistant; resistance to isoniazid; resistant to isoniazid; Isoniazid resistance; drug-sensitive; Prevalence; innovate; innovative; innovation; resistant; Resistance; clinical relevance; clinically relevant; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapy; novel therapeutics; murine model; mouse model; commercial application; Antitubercular Drugs; TB drugs; anti-TB drugs; anti-tuberculosis drugs; antituberculosis drugs; tuberculosis drugs; TB therapy; TB treatment; tuberculosis therapy; tuberculosis treatment; combat; standard of care; resistance strain; resistant strain; in vitro testing; in vitro activity; drug candidate; Phase I Study; phase 1 study; Regimen; Hep G2; HepG2 cell line; HepG2; experiment; experimental research; experiments; experimental study; new drug class; novel drug class; lead optimization; lead candidate; pulmonary infections; Lung infections; side effect; Drug resistant Mycobacteria Tuberculosis; Drug resistance in Mtb; Drug resistance in Mycobacterium Tuberculosis; Drug resistant M Tuberculosis; Drug resistant Mtb; Mtb drug resistance; drug resistance M Tuberculosis; drug resistance Mycobacteria Tuberculosis; drug resistant M.tb
