Development of Gallium-Based Therapies for Pulmonary Mycobacterial Infections

肺部分枝杆菌感染的镓基疗法的开发

• 批准号: 9275424
• 负责人: BRADLEY E BRITIGAN
• 金额: --
• 依托单位: OMAHA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9275424
• 关键词: Acinetobacter; Address; Adverse effects; Aerosols; Antibiotic Resistance; Antibiotics; Bacteria; Biodistribution; Breathing; Burkholderia cepacia; Cells; Chelating Agents; Citrates; Combined Modality Therapy; Culture Media; Cytoplasm; Data; Development; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Drug resistance; Escherichia coli; Exhibits; Extreme drug resistant tuberculosis; FDA approved; Formulation; Francisella tularensis; Gallium; Goals; Growth; Health; Healthcare; Hereditary hemochromatosis; Host Defense; Human; Hypercalcemia of Malignancy; In Vitro; Infection; Interferons; Intravenous; Iron; Lactoferrin; Lead; Link; Locales; Lung; Malignant Neoplasms; Mediating; Metabolism; Methods; Microbe; Microbial Biofilms; Multi-Drug Resistance; Mycobacterium Infections; Mycobacterium tuberculosis; NBL1 gene; Nature; Pathogenesis; Pharmaceutical Preparations; Phase I Clinical Trials; Physiologic pulse; Prevalence; Process; Production; Proteins; Pseudomonas aeruginosa; Pulmonary Tuberculosis; Radiolabeled; Research; Research Design; Resistance; Route; Serum; Siderophores; Testing; Therapeutic Index; Tissues; Tobramycin; Toxic effect; Transferrin; Transition Elements; Treatment Protocols; Tuberculosis; Veterans; Virulent; Work; antimicrobial; base; cellular targeting; combat; cystic fibrosis patients; effective therapy; extensive drug resistance; extracellular; global health; high risk; improved; in vivo; insight; iron metabolism; macrophage; microbial; microbicide; monocyte; mouse model; mycobacterial; nanoparticle; new therapeutic target; novel; novel strategies; novel therapeutics; pathogen; public health relevance; targeted treatment; trafficking; tuberculosis drugs; tuberculosis treatment; uptake

DESCRIPTION (provided by applicant): Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), is a global health problem. Treatment of drug-susceptible TB involves months of therapy with multiple potentially toxic antibiotics. Treatment of TB has become even more difficult by the emergence and increasing prevalence of multi-drug resistant M.tb. This proposal focuses on the development of a novel therapy that targets M.tb iron (Fe) acquisition, a process that is critical to its ability to cause disease. Ga(NO3)3 is a FDA- approved drug for treating hypercalcemia of malignancy. It interferes with cellular Fe metabolism by competing with Fe for uptake/use. We find that Ga also decreases M.tb Fe acquisition, inhibits growth of both drug-susceptible and drug-resistant M.tb strains growing in vitro extracellularly and within human macrophages. Ga also demonstrated efficacy in murine models of M.tb infection. Intermittent systemic delivery of Ga(NO3)3 for a few days has shown minimal toxicity in humans. However, treatment of TB would likely require more sustained treatment regimens. Ways to improve targeting of Ga to infected macrophages, extend dosing intervals, or avoid systemic administration would improve Ga's therapeutic index. There have been considerable advances in recent years in the aerosol delivery of drugs to the lung, as well as cellular targeting of nanoparticles to accomplish these goals. Therefore, we hypothesize that Ga delivery by aerosol or nanoparticle to the lung could prove to be novel, well-tolerated, and effective therapies for TB that would work via disruption of M.tb Fe metabolism. In order to test the above hypothesis we propose to accomplish the following specific aims: 1. Identify forms of Ga that exhibit maximal in vitro potency against extracellular and intracellular M.tb, including MDR- and XDR-TB, with the goal of arriving at lead compounds. 2. Develop formulations of two lead Ga compounds that will allow them to be administered by inhalation for the treatment of pulmonary TB and determine their biodistribution, pharmacokinetics, toxicity and efficacy in murine models of pulmonary TB. 3. Develop nanoparticle formulations of two lead Ga compounds that will allow them to be administered for the treatment of pulmonary TB and determine their biodistribution, pharmacokinetics, toxicity and efficacy in murine models of pulmonary TB. 4. Determine mechanisms of action of the lead Ga formulations against M.tb, potential for emergence of resistance, and effect of the presence of other TB drugs on Ga anti-mycobacterial activity. RESEARCH DESIGN AND METHODOLOGY: Human monocyte-derived macrophages and murine models of TB will be employed along with fully virulent strains of M.tb. The work will emphasize: Fe and Ga acquisition by M.tb: Ga biodistribution, pharmacokinetics, toxicity; and potential bacterial target for Ga antimicrobial activity. Experimental methods employed include: development of Ga formulations suitable for aerosol or nanoparticle-mediated delivery; bacterial uptake of radiolabeled Fe and Ga, growth of M.tb in vitro and in vivo, murine models of pulmonary TB, quantitation of Ga in tissues. POTENTIAL IMPACT ON VETERAN HEALTH CARE: Veterans are at high risk for pulmonary TB. This work could lead to development of novel treatments for TB that would benefit veterans.

描述（由申请人提供）： 结核分枝杆菌（M.TB）引起的结核病（TB）是全球健康问题。药物敏感的结核病的治疗涉及多种潜在毒性抗生素的数月治疗。由于多药耐药性M.TB的出现和越来越多的患病率，结核病的治疗变得更加困难。该提案的重点是针对M.TB Iron（FE）采集的新型疗法的发展，该过程对于引起其引起的能力至关重要 疾病。 GA（NO3）3是一种用于治疗恶性高钙血症的FDA批准的药物。它通过与FE竞争摄取/使用来干扰细胞FE代谢。我们发现，GA还减少了M.TB Fe的获取，抑制了药物易感和耐药的M.TB菌株的生长，并在人类巨噬细胞内生长。 GA还显示出在M.TB感染的鼠模型中的功效。几天内，GA（NO3）3的全身性传递（NO3）3在人类中的毒性很小。但是，结核病的治疗可能需要更多的持续治疗方案。改善GA靶向感染巨噬细胞，扩展给药间隔或避免全身给药的方法将改善GA的治疗指数。近年来，在肺部的气溶胶输送以及纳米颗粒的细胞靶向以实现这些目标方面取得了长足的进步。因此，我们假设气溶胶或纳米颗粒向肺部传递的GA可以被证明是新颖，耐受性且有效的结核病疗法，可以通过破坏M.TB Fe代谢而起作用。为了检验上述假设，我们建议实现以下特定目的：1。确定对针对细胞外和细胞内M.TB（包括MDR-和XDR-TB）表现出最大体外效力的GA形式，目的是到达铅化合物。 2。开发两种铅GA化合物的制剂，可以通过吸入来治疗肺结核，并确定其生物分布，药代动力学，毒性和疗效在肺结核的鼠模型中。 3。开发两种铅GA化合物的纳米颗粒制剂，这些制剂将允许它们用于治疗肺结核，并确定其生物分布，药代动力学，毒性和疗效在肺结核的鼠模型中。 4。确定铅ga公式对M.TB的作用机理，抗药性的潜力以及其他结核病药物对GA抗细菌活性的影响。研究设计和方法论：将采用人类单核细胞衍生的巨噬细胞和TB的鼠模型，以及M.TB的全毒素菌株。这项工作将强调：M.TB的Fe和GA获取：GA生物分布，药代动力学，毒性； GA抗菌活性的潜在细菌靶标。采用的实验方法包括：适用于气溶胶或纳米颗粒介导的递送的GA制剂的开发；放射性标记的Fe和Ga的细菌摄取，体外M.TB的生长和体内的生长，肺结核的鼠模型，组织中GA的定量。对退伍军人卫生保健的潜在影响：退伍军人对肺结核的风险很高。这项工作可能导致为TB的新型治疗发展，这将使退伍军人受益。