Mycobacterium tuberculosis (MTB) is probably the most ubiquitous microbial pathogen in the world today infecting one-third of the total population and causing millions of active tuberculosis (TB) cases each year. The economic costs are substantial and more than one million people die of TB infections each year. Before the arrival of antimicrobial therapy, TB was one of leading causes of human deaths with high mortality rates common in untreated cases of active TB infections. With the discovery of effective drugs against the disease, it became possible to cure the illness. However, antimicrobial resistance has been rising over time. Multidrug-resistant (MDR) and now extensively drug-resistant (XDR) strains that resist most first-line and second-line agents are appearing that are difficult to successfully treat. The isothiazoloquinolone (ITQ) ACH- 702 was shown to have antibacterial activity against both non-dividing and biofilm staphylococci and to be active against MTB including MDR/XDR strains with minimum inhibitory concentrations (MICs) of 1 5g/mL or less. These data suggested the potential of ITQs in shortening the duration of treatment for susceptible strains, in killing latent MTB in the host, and in effective therapy for MDR/XDR strains. However, ACH-702 was found to have suboptimal pharmacokinetic (PK) properties that precluded development as an oral agent. A prototype analog ACH-0141998, a hydroxythienoquinolone (HTQ), demonstrated improved metabolic stability and suggests a path forward to further analogs with better safety profiles and PK properties capable of supporting oral dosing. In Phase I, we will generate a series of HTQ analogs and evaluate them in a series of in vitro assays and select candidates for further advancement. The ultimate goal of this Phase I proposal is to identify a compound(s) that has metabolic stability and improved antibacterial activity against MTB including MDR/XDR strains. In Phase II, we will initiate in vivo testing including PK studies, acute and repeat-dose animal toxicity studies, and assessment of effectiveness in animal models.
Public Health Relevance: Mycobacterium tuberculosis (MTB) is a major global health concern. The spread of multidrug-resistant MDRTB isolates threatens to undermine our ability to treat these infections. The overall goal of this project is to identify antimicrobial compounds that have the potential to successfully treat both wild-type and MDRTB isolates.
Thesaurus Terms: Aids Virus; Acquired Immune Deficiency Syndrome Virus; Acquired Immunodeficiency Syndrome Virus; Acute; Animal Model; Animal Models And Related Studies; Animals; Anti-Bacterial Agents; Anti-Retroviral Agents; Antibacterial Agents; Antibiotic Therapy; Antibiotic Treatment; Antimicrobial Resistance; Antimicrobial Resistant; Antiretroviral Agents; Antitubercular Agents; Antitubercular Drugs; Bacterial Dna; Biochemical; Biological; Cell Line; Cell Lines, Strains; Cellline; Cessation Of Life; Chemical Structure; Chemicals; Dna Replication; Dna Synthesis; Dna Biosynthesis; Data; Death; Development; Disease; Disorder; Dose; Drug Interactions; Drug Kinetics; Drug Resistance, Multiple; Drug Resistant, Multiple; Drug Resistance; Drugs; Effectiveness; Exhibits; Extreme Drug Resistant Tuberculosis; Extremely Drug Resistant Tuberculosis; Genus Mycobacterium; Genus Staphylococcus; Goals; Hiv; Htlv-Iii; Human; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type Iii; Human T-Cell Lymphotropic Virus Type Iii; Human T-Lymphotropic Virus Type Iii; Human, General; In Vitro; Infection; Intermediary Metabolism; Killings; Lav-Htlv-Iii; Lead; Lymphadenopathy-Associated Virus; Lytotoxicity; M. Tb; M. Tuberculosis; M.Tb; M.Tuberculosis; Metbl; Mammalian Cell; Man (Taxonomy); Man, Modern; Medical; Medication; Metabolic; Metabolic Processes; Metabolism; Microbial Biofilms; Microbiology; Minimum Inhibitory Concentration Measurement; Minimum Inhibitory Concentrations; Modification; Morbidity; Morbidity - Disease Rate; Mortality; Mortality Vital Statistics; Multi-Drug Resistance; Multidrug Resistance; Mycobacterium; Mycobacterium Tuberculosis; Oral; Organism; Patients; Pb Element; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacokinetics; Phase; Population; Property; Property, Loinc Axis 2; Public Health; Quinolone Resistant; Regimen; Research; Resistance; Resistance To Multi-Drug; Resistance To Multidrug; Resistance To Multiple Drug; Resistance To Antimicrobial; Resistant To Multiple Drug; Resistant To Multi-Drug; Resistant To Multidrug; Route; Safety; Science Of Microbiology; Series; Side; Staphylococcus; Testing; Time; Toxic Effect; Toxicities; Treatment Period; Tuberculosis; Tuberculostatic Agents; Virus-Hiv; Work; Xdr-Tuberculosis; Analog; Anti-Bacterial; Anti-Microbial; Anti-Microbial Resistance; Anti-Microbial Resistant; Anti-Retroviral; Anti-Tuberculosis; Antibacterial; Antimicrobial; Antiretroviral; Antituberculosis; Base; Biofilm; Chemotherapy; Cultured Cell Line; Cytotoxic; Cytotoxicity; Disease/Disorder; Disseminated Tb; Disseminated Tuberculosis; Drug Resistant; Drug/Agent; Economic Cost; Effective Therapy; Efficacy Testing; Global Health; Heavy Metal Pb; Heavy Metal Lead; Improved; In Vitro Assay; In Vivo; Indexing; Living System; Meetings; Microbial; Model Organism; Multi-Drug Resistant; Multidrug Resistant; Novel; Pathogen; Prototype; Public Health Medicine (Field); Public Health Relevance; Quinolone Resistance; Resistance To Drug; Resistance To Anti-Microbial; Resistance To Quinolone; Resistant; Resistant Strain; Resistant To Drug; Resistant To Anti-Microbial; Resistant To Antimicrobial; Resistant To Quinolone; Scaffold; Scaffolding; Treatment Days; Treatment Duration; Treatment Of Bacterial Diseases; Treatment Of Bacterial Infectious Disease; Tuberculosis Treatment; Tuberculous Spondyloarthropathy
