Structural Modification of Daptomycin to Allow Anti-Pseudomonas Activity

 描述（由申请方提供）：假单胞菌是一种常见的需氧、革兰氏阴性球杆菌。目前对铜绿假单胞菌的关注是该生物体作为医院获得性肺炎的非常常见的原因的频率以及治疗它的新出现的困难。自从抗生素出现以来，铜绿假单胞菌已经对通常的治疗产生了渐进性耐药性。铁载体（“铁载体”）分子靶向技术将铜绿假单胞菌的专性铁需求和铁觅食机制转化为治疗剂。细菌铁的获得对于致病性是必不可少的，并且为开发微生物选择性疗法提供了一个有吸引力且很少使用的靶标。由于选择性铁载体的识别和运输需要细菌的生长优势，我们将测试铁载体先前显示的抗生素靶向假单胞菌的活性。铁载体靶向的许多尝试都失败了，因为铁载体与天然配体的结构匹配不良。Hsiri Therapeutics的化学家将分子识别作为设计铁霉素-抗生素缀合物的主要标准。通过这些方法，Hsiri Therapeutics，LLC最近证明，以前的革兰氏阳性特异性抗生素达托霉素可以被修饰用于治疗革兰氏阴性细菌鲍曼不动杆菌。这种转化是通过向达托霉素分子中加入靶向分子（铁载体化合物）来完成的。与达托霉素连接的铁载体被设计为对不动杆菌具有特异性，并且实现了这种特异性。同样，Hsiri的科学家们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体外和体内化合物的初步表征。我们通过四个具体目标的方法将扩展我们用三足儿茶酚-肠杆菌素模拟物与β-内酰胺抗生素所做的工作，并将其扩展到达托霉素。一旦纯化，将用标准方法评估这种新分子的体外和体内活性。此外，将使用该化合物评价小鼠中的详细耐受性，并将进行细菌清除研究（也称为细菌负荷研究），以确保在具有假单胞菌的实验性鼠脓毒症模型中完全杀死和清除细菌。

 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.