Novel cyclic lipopeptides for treating gram negative bacterial infections

 描述（由申请人提供）：住院患者发生多重耐药（MDR）细菌引起的感染的风险较高。根据美国传染病学会的MDR，革兰氏阴性病原体如铜绿假单胞菌、A。产生鲍曼不动杆菌和超广谱β-内酰胺酶的肠杆菌科尤其成问题，具有高的可归因死亡率和独特的毒力或耐药性因素。由这些病原体引起的感染由于抗生素抗性和对宿主防御和抗微生物治疗具有抗性的生物膜的形成而非常难以治疗。细菌生物膜是治疗慢性伤口感染的关键挑战。慢性伤口对感染的发展特别敏感，并且细菌生物膜涉及伤口感染和那些伤口愈合失败。鉴于问题的严重性，不可否认且迫切需要对耐多药革兰氏阴性病原体具有活性并能够调节细菌生物膜形成和维持的新抗生素。为了满足发现用于局部应用并有效对抗耐多药革兰氏阴性细菌（包括其生物膜）的新型抗菌剂的需求，我们提出设计和合成基于杀镰孢菌素/LI-F天然产物的新型环状脂肽。我们最近的突破性发现表明，这些环脂肽的总体疏水性和净正电荷的增加提高了它们对革兰氏阴性细菌的活性。效力的改善在针对细菌生物膜的活性中特别明显，因为前导肽3显示出针对铜绿假单胞菌和A.鲍曼不动杆菌生物膜重要的是，导致更疏水和带正电荷的类似物的结构变化不会导致非特异性毒性增加。在这个提议中，我们的总体目标是进一步修饰环脂肽3，以优化其抗菌/抗菌膜活性，并将非特异性毒性降至最低。在R21阶段，我们将利用组合化学与筛选试验相结合，以确定具有高效力的环状脂肽先导化合物，其对耐药和生物膜MDR革兰氏阴性菌具有高效力，并且具有低非特异性毒性。在R33阶段，我们将：a）开发基于明胶水凝胶的局部应用的最佳递送系统，B）确定这些肽的作用模式，以及c）评估优化的肽/水凝胶制剂在猪伤口感染模型中的治疗潜力。一旦完成，拟议的研究将导致一类新的抗菌肽局部应用，可以推进到临床研究。一旦完成，拟议的研究将导致一类新的抗菌肽局部应用，可以推进到临床研究。

 DESCRIPTION (provided by applicant): Hospitalized patients are at high risk for developing infections caused by multidrug-resistant (MDR) bacteria. According to the Infectious Diseases Society of America MDR Gram-negative pathogens such as P. aeruginosa, A. baumannii and extended-spectrum b-lactamase producing Enterobacteriaceae are especially problematic with high attributable mortality rates, and unique virulence or drug-resistance factors. Infections caused by these pathogens are exceedingly difficult to treat due antibiotic resistance and formation of biofilms that are resistant to host defense and antimicrobial treatments. Bacterial biofilms are a key challenge in treating chronic wound infections. Chronic wounds are particularly susceptible to the development of infections and bacterial biofilms are implicated in both the infection of wounds and failure of those wounds to heal. Given the severity of the problem, there is an undeniable and urgent need for new antibiotics active against MDR Gram-negative pathogens and capable of modulating bacterial biofilm formation and maintenance To address the need for the discovery of novel antibacterial agents for topical application and effective against MDR Gram-negative bacteria, including their biofilms, we propose to design and synthesize novel cyclic lipopeptides based on fusaricidin/LI-F natural products. Our recent breakthrough finding have shown that that the increase in overall hydrophobicity and net positive charge of these cyclic lipopeptides improved their activity against Gram-negative bacteria. The improvement in potency is particularly evident in the activity against bacterial biofilms, as the lead peptide 3 showed promising in vitro and in vivo activities against P. aeruginosa and A. baumannii biofilms. Importantly, structural changes resulting in more hydrophobic and positively charged analogues did not lead to increased nonspecific toxicity. Within this proposal, our overall goal is to further modify cyclic lipopeptide 3 to optimize its antibacterial/antibiofilm activity and to minimize nonspecific toxicity. Within the R21 phase we will utilize combinatorial chemistry in conjunction with screening assays to identify cyclic lipopeptide leads with high potency against planktonic and biofilm MDR Gram-negative bacteria and low nonspecific toxicity. In the R33 phase we will: a) develop an optimal delivery system for topical application based on gelatin hydrogels, b) determine the mode of action of these peptides, and c) assess the therapeutic potential of an optimized peptide/hydrogel formulation in a porcine wound infection model. Once completed, the proposed research will lead to a new class of antibacterial peptides for topical application that can be advanced to clinical studies. Once completed, the proposed research will lead to a new class of antibacterial peptides for topical application that can be advanced to clinical studies.