Structural Modification of Daptomycin to Allow Anti-Pseudomonas Activity

达托霉素的结构修饰以实现抗假单胞菌活性

• 批准号: 9136249
• 负责人: MARVIN J MILLER
• 金额: $ 20.22万
• 依托单位: HSIRI THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9136249
• 关键词: Acinetobacter; Acinetobacter baumannii; Active Biological Transport; Aerobic; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Area; Bacteria; Biological Assay; Chemistry; Coupling; Daptomycin; Data; Development; Dose; Ensure; Enterobactin; Enzymes; Frequencies; Gram-Negative Bacteria; Gram-Positive Bacteria; Grant; Growth; In Vitro; Investigation; Iron; Ligands; Link; Methods; Microbe; Modeling; Modification; Monobactams; Mus; Nosocomial pneumonia; Organism; Pathogenicity; Pharmacologic Substance; Pharmacology; Phase; Production; Pseudomonas; Pseudomonas aeruginosa; Resistance; Scientist; Sepsis; Siderophores; Specificity; Succinates; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Translating; Universities; Work; antibiotic design; base; beta-Lactamase; design; drug development; experience; in vitro activity; in vivo; killings; liquid chromatography mass spectrometry; mimetics; molecular recognition; novel; novel therapeutics; pre-clinical; public health relevance; resistance mechanism

 DESCRIPTION (provided by applicant): Pseudomonas is a common aerobic, gram-negative, coccobacillis. Current concerns with P. aeruginosa are both the frequency of the organism as a very common cause of nosocomial pneumonia and the emerging difficulty in treating it. Since the advent of antibiotics, P. aeruginosa has developed progressive resistance to the usual treatments. The siderophore ("iron carrier") molecule targeting technology translates P. aeruginosa's obligate iron needs and mechanisms for iron foraging into a therapeutic agent. Bacterial iron acquisition is essential for pathogenicity and provides an attractive and little-use target for developing microbe-selective therapeutics. Because of selective siderophore recognition and transport needed for bacterial growth advantage, we will test a siderophore previously shown to be active in targeting antibiotics to pseudomonas. Many attempts at siderophore targeting have failed because of poor structural matching of the siderophore to the native ligands. Hsiri Therapeutics' chemists have put molecular recognition as the primary criterion for designing sideromycin-antibiotic conjugates. By these methods, Hsiri Therapeutics, LLC has recently demonstrated that the previously gram-positive specific antibiotic, daptomycin, can be modified for treatment against the gram-negative bacterium, Acinetobacter baumannii. This transformation was done with the addition of a targeting molecule, a siderophore compound, to the daptomycin molecule. The siderophore linked to the daptomycin was designed to be specific for acinetobacter and this specificity was achieved. In like manner, Hsiri scientists have designed an antibiotic substitution that targets Pseudomonas aeruginosa. This proposal would support the synthesis of this agent and the initial characterization of the compound in vitro and in vivo. Our approach through four specific aims will be to extend the work we have done with the tripodal catecholate - entereobactin mimetic with beta-lactam antibiotics and extend it to daptomycin. Once purified, this new molecule will be assessed with standard methods for both in vitro and in vivo activity. Additionally, detailed tolerability in mic will be evaluated with this compound and a bacterial clearance study (aka bacterial burden study) will be done to ensure full bacterial killing and clearance in an experimental murine sepsis model with pseudomonas.

 说明(申请人提供)：假单胞菌是一种常见的需氧革兰氏阴性球菌。目前对铜绿假单胞菌的关注既是这种微生物作为医院内肺炎的一种非常常见的原因的频率，也是治疗它的新出现的困难。自从抗生素出现以来，铜绿假单胞菌对常规治疗逐渐产生抗药性。铁载体(“铁载体”)分子靶向技术将铜绿假单胞菌特有的铁需求和铁觅食机制转化为治疗剂。细菌铁的获取对致病性是必不可少的，并为开发微生物选择性治疗药物提供了一个有吸引力且很少使用的靶点。由于细菌生长优势所需的选择性铁载体识别和运输，我们将测试以前被证明在将抗生素靶向假单胞菌方面具有活性的铁载体。许多以铁载体为靶点的尝试都失败了，因为铁载体与天然配体的结构匹配不佳。西日治疗公司的化学家将分子识别作为设计铁霉素-抗生素结合物的首要标准。通过这些方法，Hsiri Treeutics，LLC最近证明，以前革兰氏阳性的特异性抗生素达托霉素可以被改造成治疗革兰氏阴性菌鲍曼不动杆菌。这种转化是通过在达托霉素分子中添加靶向分子-铁载体化合物来完成的。与达托霉素相连的铁载体被设计成对不动杆菌具有特异性，并实现了这种特异性。以同样的方式，Hsiri的科学家设计了一种针对铜绿假单胞菌的抗生素替代品。这一建议将支持该试剂的合成和化合物的体外和体内初步表征。我们的方法将通过四个具体目标来扩展我们用β-内酰胺类抗生素模拟三脚架儿茶酚-肠抑素所做的工作，并将其扩展到达托霉素。一旦纯化，这种新分子将用标准方法进行体外和体内活性评估。此外，将使用该化合物评估小鼠的详细耐受性，并将进行细菌清除研究(又名细菌负荷研究)，以确保在带有假单胞菌的实验性小鼠脓毒症模型中完全杀灭和清除细菌。