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

• 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
• 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

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 多重耐药细菌已演变成可用资源短缺的全球危机 抗生素。面对日益增加的压力，必须发现和设计下一代 新型抗微生物组合物的组合。非特异性相互作用是最常见的相互作用之一 避免抗菌素耐药性的有前途的方法。这种相互作用包括库仑 带相反电荷的基团之间的吸引力和疏水-疏水相互作用。它 涉及抗菌剂攻击细菌的一系列协调和级联事件。 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 抗菌剂对细菌的杀伤作用以及对真核细胞的细胞相容性。 我们建议设计沿着大分子链聚集的局部面部两亲性作为 对革兰氏阴性菌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。首先它采用了面部两亲性 宿主防御肽，但不一定具有螺旋构象；其次它没有 需要克服抗菌药物可能不可能实现的全局构象排列 聚合物需要适应以使表面具有两亲性。这种新的高分子设计 抗菌剂通过含有一系列多环的新型阳离子聚合物得到证明 天然产物包括松香酸、胆酸和熊果酸，它们是三酸的代表， 四环和五环化合物。我们定义面部两亲指数（FAI）来理解 疏水性和带电基团的组合以及横截面积 需要穿透外叶并进一步破坏细菌的细胞膜。这 最大的贡献是将面部两亲性与细胞组成相关联，以设计选择性 抗菌疗法可能为对抗令人烦恼的细菌耐药性开辟新途径。