Antimicrobial activity of pH-activated polypeptides toward H. pylori

 描述(申请人提供)：幽门螺杆菌感染是胃炎、胃溃疡和胃癌的主要病因。世界上约50%的人口感染幽门螺杆菌，幽门螺杆菌感染是全球主要的公共卫生负担。对于感染的患者，建议使用多种抗生素根除幽门螺杆菌，已成为治疗幽门螺杆菌感染的一线药物。而抗生素 治疗对根除幽门螺杆菌感染是有效的，但其疗效正在逐渐下降。抗生素耐药是治疗失败的主要原因，已成为幽门螺杆菌感染治疗面临的最大挑战。迫切需要开发新的治疗方法，能够根除幽门螺杆菌，但不容易产生耐药性。合成抗菌寡肽(AMP)是近年来出现的一种新型抗菌剂，用于对抗耐多药微生物。然而，这些多肽对幽门螺杆菌的杀灭活性很少被测试。该方案的总体目标是设计一类在酸性条件下选择性杀死幽门螺杆菌的多肽，并探索其在根除幽门螺杆菌感染及其相关胃病方面的治疗潜力。在特定的目标1，我们将测定具有独特螺旋结构的多肽的抗微生物活性。我们将设计和开发能够在酸性pH下从非螺旋结构转化为螺旋结构的多肽，以选择性地杀死幽门螺杆菌。在具体目标2中，我们将探索这些pH激活的多肽在根除幽门螺杆菌感染和幽门螺杆菌引起的胃病方面的抗微生物潜力。我们还将测定这些多肽对耐药幽门螺杆菌菌株的杀菌活性。这些体外、细胞和体内动物实验将为多肽作为根除幽门螺杆菌感染的有效药物的发展提供新的见解，并为根除幽门螺杆菌感染和预防幽门螺杆菌介导的胃病的非传统治疗提供新的信息。

 DESCRIPTION (provided by applicant): Helicobacter pylori infection is the major etiological factor in the development of gastritis, gastric ulcers, and gastric carcinoma. About 50% of the world's population is infected with H. pylori and H. pylori infection presents a major global publi health burden. Eradication of H. pylori with more than one antibiotic is recommended for infected patients and has become the first line treatment for H. pylori infection. While antibiotic therapy is effective in eradicating H. pylori infection, its efficacy is gradually decreasing. Antibiotic resistance is the major cause of treatment failure and has become the most evident challenge to treatment of H. pylori infection. It is urgently required to develop novel therapies that are able to eradicate H. pylori but not easily susceptible to resistance. Synthetic antimicrobial oligo peptides (AMP) have recently emerged as novel antimicrobial agents in combating multidrug resistant microbes. However, the microbiocidal activity of these peptides on H. pylori has rarely been tested. The overall goal of this proposal is to design a new class of polypeptides that would selectively kill H. pylori under acidic conditions and explore their therapeutic potentials in eradication of H. pylori infection and its associated gastric diseases. n Specific Aim 1, we will determine the anti-microbial activity of polypeptides with unique helical structure. We will design and develop polypeptides that can be converted from a non-helical structure to a helical structure under acidic pH to selectively kill H. pylori. In Specific Aim 2, e will explore the anti-microbial potential of these pH-activated polypeptides in eradication of H. pylori infection and H. pylori-induced gastric diseases. We will also determine the bactericidal activity of these peptides toward antibiotic-resistant H. pylori strains. These in vitro, cell-base, and in vivo animal experiments will provide new insights into the development of polypeptides as effective agents for eradication of H. pylori infection and also provide new information on nontraditional therapy for the eradication of H. pylori infection and the prevention H. pylori- mediated gastric diseases.