I-Corps: Mitigating Multidrug Resistant Bacterial Infections with Biocompatible and Environmentally Benign Nanoantibiotics

I-Corps：利用生物相容性且对环境无害的纳米抗生素减轻多重耐药细菌感染

• 批准号: 2306943
• 负责人: Hongjun Liang
• 金额: $ 5万
• 依托单位: Texas Tech University Health Science Center
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2306943&HistoricalAwards=false
• 关键词: Corps; Mitigating; Multidrug; Resistant; Bacterial

The broader impact/commercial potential of this I-Corps project is the development of antibiotics to mitigate multidrug resistant bacterial infections. Antibiotic resistance is a global public health crisis, and “one of our most serious health threats” according to the CDC. The world has witnessed a surge of superbugs that elude one or more antibiotics at an alarming rate. This situation is exacerbated by the lack of new antibiotics in the pipeline and increasing accumulation of artificial antibiotic wastes in natural habitats that further accelerates resistome development. Membrane-active antimicrobials (MAAs) have been widely anticipated to be promising candidates for new antibiotics. However, toxicity is one of the biggest barriers to the translation of MAAs to the market, of which the indiscriminate hydrophobic interaction that disrupts both bacterial and mammalian membranes is a major contributing factor. The proposed technology uses hydrophilic nanoantibiotics that kill bacteria, including multidrug resistant (MDR) bacterial strains, highly efficiently without damaging mammalian cells. In addition, they have been shown to undergo rapid degradation and deactivation by enzymes that exist in natural habitats when released as wastes. This technology potentially may be used to solve the crisis of antibiotic resistance.This I-Corps project is based on the development of biocompatible and environmentally benign nanoantibiotics. The proposed technology has demonstrated that assembly of hydrophilic and antimicrobial inactive linear-chain polymers into nanostructured polymer molecular brushes (PMBs) turns “ON” their antimicrobial activities collectively, while disassembly of the nanostructured PMBs turns the acquired activities “OFF”. In addition, nanoantibiotics have been shown to kill bacteria by selectively disrupting the bacterial membranes while remaining benign to mammalian cells. Because this mode of damage acts on bacterial membranes instead of targeting biosynthetic pathways as conventional antibiotics do, it is extremely difficult for bacteria to produce resistant strains. Nanoantibiotics low toxicity to mammalian cells further suggests that they have a great potential for clinical use. In addition, the environmentally degradable nanoantibiotics help solve the long-standing problem of continuous accumulations of antibiotic wastes in natural habitats, which alters the structure and function of the microbial community in sensitive ecosystems, threatens food and water security, and accelerates the development of the resistome. The development of environmentally degradable nanoantibiotics may represent a milestone in the search for new antibiotics and may have commercialization potential to fight drug-resistant bacterial infections.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该I-Corps项目的更广泛的影响/商业潜力是开发抗生素来减轻多药耐药细菌感染。抗生素耐药性是全球公共卫生危机，也是“我们最严重的健康威胁之一”。全世界目睹了超级细菌的激增，以惊人的速度洗脱一种或多种抗生素。在管道中缺乏新的抗生素以及人工抗生素废物在自然栖息地中的积累增加，这种情况加剧了这种情况，从而进一步加速了反应性的发展。膜活性抗菌剂（MAA）已被广泛预期将成为新抗生素的候选人。但是，毒性是将MAA转换为市场的最大障碍之一，在这种障碍中，杂物化的疏水相互作用会破坏细菌和哺乳动物的膜是主要的促成因素。提出的技术使用杀死细菌的亲水性纳米抗生素，包括耐多药（MDR）细菌菌株，高效而不会损害哺乳动物细胞。此外，已经证明它们会通过自然栖息地中存在的酶迅速降解和失活。该技术可能用于解决抗生素耐药性危机。这个I-Corps项目基于生物相容性和环境良性纳米抗生素的发展。该提出的技术表明，亲水性和抗菌无活性的线性链聚合物组装成纳米结构的聚合物分子刷（PMB）集体打开其抗菌活性，而对纳米结构的PMB进行拆卸，将其拆分为“纳米结构的PMB”。此外，纳米抗生素已被证明可以通过选择性破坏细菌机制来杀死细菌，同时保持对哺乳动物细胞的良性。由于这种损伤模式作用于细菌培养基，而不是像常规抗生素那样靶向生物合成途径，因此细菌产生抗性菌株非常困难。纳米抗生素对哺乳动物细胞的低毒性进一步表明它们具有巨大的临床使用潜力。此外，环境降解的纳米抗生素有助于解决自然栖息地中抗生素废物连续积累的长期问题，从而改变了微生物群落在敏感生态系统中的结构和功能，威胁食品和水安全，并加速了恢复的发展。可环境降解的纳米抗生素的发展可能是寻找新抗生素的一个里程碑，并且可能具有抵抗耐药细菌感染的商业化潜力。该奖项反映了NSF的法定任务，并认为通过使用该基金会的知识分子和更广泛影响的评估来评估Criteria，并被认为是值得通过评估的支持。