DEVELOPMENT OF BENZOTRIAZINE OXIDES AS THERAPEUTICS FOR DRUG RESISTANT TUBERCULOS
Peter B Madrid
Sri International, Menlo Park, Ca 94025-3493
Grant 1R56AI090817-01 from National Institute Of Allergy And Infectious Diseases
Keywords: 1, 2, 4-Benzotriazin-3-amine, 1, 4-dioxide; 3-amino-1, 2, 4-benzotriazine-1, 4-dioxide; 4-Pyridinecarboxylic acid, hydrazide; Adverse effects; Animal Model; Animal Models and Related Studies; Anti-Bacterial Agents; Anti-Cancer Agents; Anti-Tumor Agents; Anti-Tumor Drugs; Antibacterial Agents; Antibiotic Agents; Antibiotic Drugs; Antibiotics; Antineoplastic Agents; Antineoplastic Drugs; Antineoplastics; Antiproliferative Agents; Antiproliferative Drugs; Antitubercular Agents; Antitubercular Drugs; Assay; Bacillus; Bacillus (bacterium); Benemycin; Benzotriazines; Bioassay; Bioavailability; Biologic Assays; Biologic Availability; Biological Assay; Biological Availability; Cancer Drug; Cells; Cessation of life; Chemistry, Pharmaceutical; Chemotherapeutic Agents, Neoplastic Disease; Chicago; Collaborations; Complex; Compliance behavior; Cytolysis; Data; Death; Dehydrogenases; Development; Development and Research; Disease; Disorder; Dose; Drug Combinations; Drug Kinetics; Drug resistance; Drugs; Electron Transport; Electrons; Ensure; Enzymes; Evaluation; Extreme drug resistant tuberculosis; Extremely drug resistant tuberculosis; Family; Frequencies (time pattern); Frequency; Generalized Growth; Goals; Growth; Illinois; In Vitro; Infection; International; Isonicotinic Acid Hydrazide; Lead; Length; Lung Granuloma; Lysis; Lytotoxicity; M. tb; M. tuberculosis; M.tb; M.tuberculosis; Mammals, Mice; Medication; Medicinal Chemistry; Metabolic; Methods and Techniques; Methods, Other; Mice; Miscellaneous Antibiotic; Modeling; Molecular; Multidrug-Resistant Tuberculosis; Murine; Mus; Mycobacterium tuberculosis; Negative Beta Particle; Negatrons; Oral; Oxides; Oxidoreductase; Patient Compliance; Patient Cooperation; Pb element; Permeability; Pharmaceutic Chemistry; Pharmaceutic Preparations; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacokinetics; Phase; Physiologic Availability; Programs (PT); Programs [Publication Type]; Property; Property, LOINC Axis 2; Protocols, Treatment; R & D; R&D; RGM; Reductases; Regimen; Resistance; Resistance development; Resistant development; Rifadin; Rifampicin; Rifampin; Rifamycin, 3-(((4-methyl-1-piperazinyl)imino)methyl)-; Rimactane; Safety; Screening procedure; Series; Solubility; Staging; Structure-Activity Relationship; Techniques; Testing; Therapeutic; Tirazone; Tissue Growth; Toxic effect; Toxicities; Treatment Compliance; Treatment Protocols; Treatment Regimen; Treatment Schedule; Treatment Side Effects; Tuberculosis; Tuberculosis, MDR; Tuberculosis, Multi-Drug Resistant; Tuberculosis, MultiDrug Resistance; Tuberculosis, Multidrug-Resistant; Tuberculostatic Agents; Tumor-Specific Treatment Agents; United States; Universities; Vulnerable Populations; XDR-Tuberculosis; analog; anti-bacterial; anti-tuberculosis; antibacterial; anticancer agent; anticancer drug; antituberculosis; bactericidal; bactericide; base; bioavailability of drug; chemical structure function; combat; compliance cooperation; counterscreen; cytotoxicity; design; designing; developing resistance; disease/disorder; disseminated TB; disseminated tuberculosis; drug development; drug resistant; drug/agent; effective therapy; electron transfer; experience; heavy metal Pb; heavy metal lead; improved; in vitro activity; in vivo; innovate; innovation; innovative; isoniazid; model organism; mouse model; neglect; novel; ontogeny; patient adherence; pharmacokinetic characteristic; pre-clinical; preclinical; programs; pulmonary granuloma; research and development; resistance mechanism; resistance to Drug; resistant; resistant mechanism; resistant strain; resistant to Drug; screening; screenings; side effect; structure function relationship; therapy adverse effect; therapy compliance; therapy cooperation; therapy duration; tirapazamine; treatment adverse effect; tuberculosis drugs; tuberculous spondyloarthropathy
Relevance: The goal of the project is to create improved treatment regimens for XDR/MDR-TB infections that will be shorter and have fewer side effects. The development of a shorter, more effective treatment regimen will increase patient compliance and therefore slow down the emergence of drug resistance and protect vulnerable populations not only in the United States but worldwide
Project start date: 2010-08-30
Project end date: 2011-08-29
Budget start date: 30-AUG-2010
Budget end date: 29-AUG-2011
PFA/PA: RFA-AI-09-026
1R56AI090817-01 (2010): $1046974
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Peter B Madrid
DUAL ACTION INHIBITORS OF GYRASE BETA AND HISTIDINE KINASES AS BROAD-SPECTRUM ANT
Peter B Madrid
Sri International, Menlo Park, Ca 94025-3493
Grant 5U01AI082070-02 from National Institute Of Allergy And Infectious Diseases
Abstract: 2. U01 A108201 5-01 ´Broad Spectrum Therapeutics Targeting Resolvase Enzymes" The goal of this project is to develop broad-spectrum antibiotics that are dual action inhibitors of gyrase B (GyrB) and histidine protein kinases (HPKs). GyrB is an established antibiotic drug target essential for bacterial viability and HPK5 are an emerging drug target involved in many virulence mechanisms. Though functionally distinct, these proteins are both members of the GHKL protein superfamily with the structurally defining feature of an unconventional ATP-binding fold. We will use a structure-based multi-target design strategy to identify low molecular weight 22o scaffolds with the potential to bind deeply into this conserved ATP-binding pocket. Based on the purchased from an American company, thereby advancing the goals of the ARRA. proiect will generate lobs for more than four people (4 FTE5) and one piece of equipment will be Perform Hit-to-Lead optimizations for new broad spectrum biodefense antibiotics. Funding of this Characterize the functional and antibiotic activities of the dual GyrB/QseC inhibitors; and 3. based, information-driven approach to identify dual GyrB/QseC inhibiting candidate scaffolds; 2. N lAID Category A pathogen, Francisella tularensis. The specific aims are to 1. Use a structure- proposal is to develop lead candidate compounds targeting GyrB and the HPK, QseC, of the GHKL protein family inhibitors. Based on these observations, the experimental focus of this design strategy to identify low molecular weight scaffolds as starting points for the development of owing to the multi-target activity. Preliminary experiments have validated our structure-based dually active GyrB and HPK inhibitor would be a superior antibiotic with low resistance potential structural similarities of the adenine-binding pockets of these proteins, we hypothesize that a 0)_ BCD ¿-o 0)+, 0>-0 (
Keywords: 1H-Purin-6-amine; Adenine; American; Antibiotic Agents; Antibiotic Drugs; Antibiotics; Ants; Armed Forces Personnel; Assay; Binding; Binding (Molecular Function); Binding Sites; Bioassay; Bioavailability; Biologic Assays; Biologic Availability; Biological Assay; Biological Availability; Budgets; Categories; Cell Communication and Signaling; Cell Signaling; Chemistry, Pharmaceutical; Combining Site; DNA, Supercoiled; DNA, Superhelical; DNA, Supertwisted; Development; Drug Delivery; Drug Delivery Systems; Drug Targeting; Drug Targetings; Enzymes; Equipment; F. tularensis; Francisella tularensis; Funding; Generalized Growth; Goals; Growth; Histidine; Histidine, L-isomer; Human; Human, General; In Vitro; Intention; Intracellular Communication and Signaling; L-Histidine; Lead; Libraries; Mammals, Mice; Man (Taxonomy); Man, Modern; Maximal Tolerated Dose; Maximally Tolerated Dose; Maximum Tolerated Dose; Measurement; Medicinal Chemistry; Metabolic; Mice; Military; Military Personnel; Minor; Miscellaneous Antibiotic; Modeling; Modification; Molecular Interaction; Molecular Weight; Murine; Mus; NIAID; National Institute of Allergy and Infectious Disease; Oral; Pasteurella tularensis; Pb element; Permeability; Pharmaceutic Chemistry; Pharmaceutical Chemistry; Physiologic Availability; Protein Family; Protein Kinase Inhibitors; Proteins; Reactive Site; Resistance; Resolvase; Rodent Model; Screening procedure; Signal Transduction; Signal Transduction Systems; Signaling; Sn element; Specificity; Stannum; Structure; Superhelical DNA; Testing; Tin; Tissue Growth; Toxic effect; Toxicities; Virulence; Vitamin B4; Work; analog; base; bioavailability of drug; biodefense; biological signal transduction; combinatorial; counterscreen; design; designing; experiment; experimental research; experimental study; gene product; heavy metal Pb; heavy metal lead; histidine kinase; in vitro activity; inhibitor; inhibitor/antagonist; lead series; member; ontogeny; pathogen; protein kinase inhibitor; protein-histidine kinase; research study; resistant; scaffold; scaffolding; screening; screenings; therapeutic target; virtual
Relevance: Our primary focus will be to develop antibiotic lead compounds against F. fularensis, but with the intention of producing antibiotics with the broadest spectrum of activity possible. Since two of the three Category A and ten of the eleven Category B bacterial pathogens are gram-negative, the development of new gram-negative or broad-spectrum antibiotics is imperative to adequately protect civilian and military personnel from bioterrorist attacks. fl- D..-. m¿´ =´. ..r L_1
Project start date: 2009-09-22
Project end date: 2011-08-31
Budget start date: 1-SEP-2010
Budget end date: 31-AUG-2011
PFA/PA: RFA-AI-08-001
5U01AI082070-02 (2010): $982218
1U01AI082070-01 (2009): $855306