Control of Facial Amphiphilicity to Tune Macromolecular Interactions with Bacteria

控制面部两亲性以调节大分子与细菌的相互作用

基本信息

批准号：
10304183
负责人：
Chuanbing Tang
金额：
$ 36.52万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10304183
关键词：
Adopted Advanced Development Affinity Antibiotics Antimicrobial Resistance Area Autoimmunity Bacteria Bacterial Infections Binding Cations Cell Culture Techniques Cell Death Cell membrane Cells Cellular Structures Centers for Disease Control and Prevention (U.S.)Charge Cholic Acids Communicable Diseases Computer Models Coupled Cytolysis Data Diterpenes Dyes Ensure Enterobacteriaceae Entropy Equilibrium Eukaryotic Cell Event Extravasation Face Family Gram-Negative Bacteria Hand Strength Healthcare Host Defense Human Hydrophobic Interactions Hydrophobicity Hypersensitivity Immune Immunosuppression In Vitro Incentives Infection Lead Measures Membrane Microbial Biofilms Molecular Conformation Molecular Target Multiple Bacterial Drug Resistance Mus Natural Products Pathway interactions Pentas Peptides Polymers Predisposition Process Pseudomonas aeruginosa Public Health Reproducibility Research Resistance Resistance to infection Series Side Steroids Structure System Terpenes Testing Toxic effect Toxicity Tests Work abietic acid alpha helix amphiphilicity antimicrobial antimicrobial drug antimicrobial peptide bacterial resistance base cell injury combat cost cyclic compound cytotoxic cytotoxicity design fighting flexibility hydrophilicity in vitro testing in vivo indexing innovation lipophilicity macromolecule next generation novel pathogen pressure resistance mechanism segregation success systemic toxicity ursolic acid

项目摘要

Abstract Multidrug-resistant bacteria have evolved into a global crisis on the shortage of available antibiotics. Facing the mounting pressure, it is essential to discover and design next-generation portfolios of novel antimicrobial compositions. Nonspecific interactions are among the most promising approaches for evading antimicrobial resistance. Such interactions include Coulombic attraction between oppositely charged groups and hydrophobic-hydrophobic interactions. It involves a series of coordinated and cascade events for antimicrobial agents to attack bacteria. Because of non-specificity, it would be more challenging for bacteria to develop mechanisms for resistance. On the other hand, strength and selectivity of such interactions are critical to efficacy of antimicrobial killing against bacteria as well as cytocompatibility toward eukaryotic cells. We propose to design local facial amphiphilicity clustered along a macromolecular chain as a new class of antimicrobial compositions that are particularly effective against Gram-negative pathogens. This unique macromolecular composition overcomes many deficiencies of antimicrobial peptides and antimicrobial polymers. First it adopts the facial amphiphilicity from host defense peptides, but not necessarily possessing a helical conformation; second it does not need to overcome a likely impossible global conformational arrangement that antimicrobial polymers need to adapt to make facial amphiphilicity. This new design of macromolecular antimicrobials is demonstrated with novel cationic polymers containing a series of multicyclic natural products including abietic acid, cholic and ursolic acid, which are representatives of tri-, tetra- and penta-cyclic compounds. We define a facial amphiphilic index (FAI) to understand a combination of hydrophobicity and charged groups as well as cross-sectional areas that are needed to penetrate through outer leaflets and further damage cell membranes of bacteria. The most contribution is to correlate facial amphiphilicity with cell compositions for designing selective antimicrobial therapies that could pave a new pathway to fighting vexing bacterial resistance.

抽象的在可用的情况下，多药耐药细菌已演变为全球危机抗生素。面对不断增长的压力，必须发现和设计下一代新型抗菌组合物的投资组合。非特异性互动是最多的逃避抗菌耐药性的有前途的方法。这种互动包括库仑相对电荷的组与疏水 - 综合性相互作用之间的吸引力。它涉及一系列协调和级联事件，以供抗菌剂攻击细菌。由于非特异性，细菌开发机制将更具挑战性反抗。另一方面，这种相互作用的强度和选择性对于功效至关重要针对细菌的抗菌杀伤以及对真核细胞的细胞相容性。我们建议设计沿大分子链聚集的局部面部两亲性作为一个针对革兰氏阴性剂特别有效的新型抗菌组合物病原体。这种独特的大分子成分克服了许多缺陷抗菌肽和抗菌聚合物。首先，它采用面部两亲性宿主防御肽，但不一定具有螺旋构象；第二，它没有需要克服可能不可能的全球构象安排，抗菌素聚合物需要适应面部两亲性。大分子的新设计用含有一系列多环状的新型阳离子聚合物证明了抗菌素天然产物在内的天然产物，包括Abietic Acid，Cholic和Ursolic Acid，它们是Tri-Aptivers 四和五生化合物。我们定义一个面部两亲指数（FAI），以了解疏水性和充电组以及横截面区域的结合需要穿过外部小叶并进一步损害细菌的细胞膜。这最大的贡献是将面部两亲性与用于设计选择性的细胞组成相关联抗菌疗法可以铺平一种与烦恼细菌抗性作斗争的新途径。