Host Targeted Therapy for Drug Resistant Salmonella and Francisella infection

耐药沙门氏菌和弗朗西斯氏菌感染的宿主靶向治疗

• 批准号: 9901429
• 负责人: Kristy M Ainslie
• 金额: $ 104.34万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-22 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9901429
• 关键词: ADME Study; AKT Signaling Pathway; Acetates; Acids; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Autophagocytosis; Bacteria; Bacterial Drug Resistance; Bacterial Infections; Biocompatible Materials; Biological; Biological Assay; Biomedical Engineering; Camptothecin; Categories; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chemical Structure; Chemistry; Clinical assessments; Computer software; Data; Development; Dextrans; Drug Design; Drug resistance; Encapsulated; Excipients; Excretory function; Formulation; Francisella; Francisella tularensis; Genes; Goals; Grant; Growth; Health Care Costs; Host Defense Mechanism; Human; In Vitro; Infection; Infection prevention; Institutes; Institution; Isoenzymes; Lead; Life Cycle Stages; Malignant Neoplasms; Maximum Tolerated Dose; Metabolism; Methods; Minimum Inhibitory Concentration measurement; Modeling; Multi-Drug Resistance; Mus; National Institute of Allergy and Infectious Disease; North Carolina; Oral; PDH kinase; Paclitaxel; Pathway Analysis; Pathway interactions; Phagocytes; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase I Clinical Trials; Polymers; Process; Production; Proto-Oncogene Proteins c-akt; Public Health; Research; Research Personnel; Resistance; Salmonella enterica; Salmonella infections; Salmonella typhi; Salmonella typhimurium; Structure; System; Taiwan; Testing; Therapeutic; Time; Tissue-Specific Gene Expression; Toxic effect; Toxicology; Tularemia; Universities; Virulence; absorption; analog; bacterial resistance; base; design; drug candidate; drug development; drug mechanism; drug resistant bacteria; experience; experimental study; fighting; improved; in vivo; in vivo evaluation; inhibitor/antagonist; lead candidate; lead optimization; macrophage; meetings; nanoparticulate; novel; particle; pathogen; pre-clinical; preclinical development; preclinical safety; pressure; prevent; resistant strain; safety study; scaffold; targeted treatment; therapeutic target; therapy development; transcriptome sequencing

Abstract The formation of antibacterial drug resistance is a public health crisis and has led to increaseing healthcare costs and even death. Drug resistance can occur when an antibiotic directly kills a pathogen or prevents its growth because of selective pressure. This phenomena has generated various multi-drug resistant bacterial species that are a global public health concern. Most antibacterial therapeutics target the pathogen in an attempt to clear infection. However, more recently the concept of antibacterial therapeutics that target host specific pathways has been developed. These pathways can potentially prevent infection, virulence, replication, and proliferation. Therapies that target these pathways could potentially treat traditional antibiotic resistant strains. Additionally, targeting the host instead of the pathogen could prevent the development of drug resistance because the therapy could activate pathways that fight resistance and activate the host’s defense mechanisms. Futhermore, because many pathogens take advantage of similar pathways, there is a potential for developing therapies that target a broad-spectrum of pathogens. We were one of the first groups to use a host-targeted therapeutic (HTT) for the treatment of a pathogen that is considered a Threat Level of Serious by the CDC. This HTT does not work directly on intracellular pathogens but instead targets host cell promoting pathways that result in clearance of the pathogen. Additionally, this HTT has broad-spectrum activity against pathogens including a NIAID Category A class pathogen. We have both in vitro and in vivo data showing activity and increase in survival. In order to increase activity we have encapsulated this compound in a novel biomaterial that is acid sensitive. This acid sensitivity allows for the intracellular release of encapsulated cargo. Our preliminary data shows that encapsulation of the HTT drastically enhances the efficacy of the compound compared to non-encapsulated form. In this proposal, we propose on performing medicinial chemistry on our HTT to develop a compound with increased activity. We will formulate this compound in our novel polymeric particles for both in vitro and in vivo testing. We will perform various biological assays to determine activity of optimized compounds. In order to do this, our proposal is a partnership between the University of North Carolina, National Taiwan University, and the Research Triangle Institute (RTI). This partnership will be invaluable in obtaining an optimized HTT compound that has activity against a broad spectrum of pathogens as it incoporates academic researchers in the field and RTI’s experience with drug development.

摘要 抗菌药物耐药性的形成是一个公共卫生危机，并导致越来越多的 医疗费用，甚至死亡。当抗生素直接杀死病原体或 因为选择压力阻止了它的生长。这一现象产生了各种多药耐药 细菌物种是一个全球性的公共卫生问题。 大多数抗菌治疗剂靶向病原体以试图清除感染。但更多 最近，已经开发了靶向宿主特异性途径的抗菌治疗剂的概念。这些 途径可以潜在地防止感染、毒力、复制和增殖。针对这些疾病的治疗 这些途径可以潜在地治疗传统的抗生素耐药菌株。此外，针对主机而不是 病原体可以阻止耐药性的发展，因为治疗可以激活 抵抗抵抗并激活宿主的防御机制因为许多病原体都是 由于类似途径的优势，有可能开发出针对广谱的 病原体 我们是最早使用宿主靶向治疗（HTT）治疗病原体的团队之一 疾病预防控制中心认为这是一个严重的威胁级别。这种HTT不直接作用于细胞内 病原体，而是靶向宿主细胞促进导致病原体清除的途径。此外，本发明还 该HTT具有抗病原体的广谱活性，包括NIAID A类病原体。我们有 体外和体内数据均显示活性和存活率增加。为了增加活动， 将这种化合物封装在对酸敏感的新型生物材料中。这种酸敏感性允许 细胞内释放包裹的货物。我们的初步数据表明，HTT的封装大大提高了 与未包封的形式相比增强了化合物的功效。 在这项提案中，我们建议对我们的HTT进行药物化学研究，以开发一种化合物， 活动增加。我们将在我们的新型聚合物颗粒中配制这种化合物，用于体外和体内 试验.我们将进行各种生物测定以确定优化化合物的活性。为做 这个，我们的建议是北卡罗来纳州大学，国立台湾大学和 三角研究所（RTI）。这种伙伴关系将是非常宝贵的，在获得优化的HTT化合物 它对广泛的病原体具有活性，因为它与该领域的学术研究人员合作， RTI的药物开发经验。

项目成果

Overcoming reduced antibiotic susceptibility in intracellular Salmonella enterica serovar Typhimurium using AR-12.

使用 AR-12 克服细胞内肠沙门氏菌鼠伤寒血清型中抗生素敏感性降低的问题。

• DOI: 10.1093/femsle/fnab062
• 发表时间: 2021
• 期刊: FEMS microbiology letters
• 影响因子: 2.1
• 作者: Zahid,MShamimHasan;Varma,DevikaM;Johnson,MonicaM;Landavazo,Antonio;Bachelder,EricM;Blough,BruceE;Ainslie,KristyM
• 通讯作者: Ainslie,KristyM

Formulation of host-targeted therapeutics against bacterial infections.

• DOI: 10.1016/j.trsl.2020.03.009
• 发表时间: 2020-06
• 期刊: Translational research : the journal of laboratory and clinical medicine
• 作者: Varma DM;Zahid MSH;Bachelder EM;Ainslie KM
• 通讯作者: Ainslie KM

Nano- and Microformulations to Advance Therapies for Visceral Leishmaniasis.

• DOI: 10.1021/acsbiomaterials.0c01132
• 发表时间: 2021-05-10
• 期刊: ACS BIOMATERIALS SCIENCE & ENGINEERING
• 影响因子: 5.8
• 作者: Varma, Devika M.;Redding, Elizabeth A.;Bachelder, Eric M.;Ainslie, Kristy M.
• 通讯作者: Ainslie, Kristy M.