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 项目的更广泛影响/商业潜力是开发抗生素来减轻多重耐药细菌感染，抗生素耐药性是一场全球公共卫生危机，并且根据疾病预防控制中心的说法，这是“我们最严重的健康威胁之一”。由于新抗生素的缺乏以及自然栖息地中人造抗生素废物的不断积累，进一步加速了抗药性的发展，这种情况变得更加严重。膜活性抗菌剂 (MAA) 被广泛认为是新型抗生素的有希望的候选者，然而，毒性是 MAA 进入市场的最大障碍之一，其中不加区别的疏水相互作用会破坏细菌和哺乳动物的细胞膜。所提出的技术使用高亲水性纳米抗生素，可以有效杀死细菌，包括多重耐药（MDR）细菌菌株，而且不会损害哺乳动物细胞。此外，它们已被证明会快速降解。该技术可能用于解决抗生素耐药性危机。该项目基于生物相容性和环境友好的纳米抗生素的开发。将亲水性和抗菌性非活性直链聚合物组装成纳米结构聚合物分子刷（PMB），共同“开启”其抗菌活性，而纳米结构聚合物分子刷的分解此外，纳米抗生素已被证明可以通过选择性破坏细菌膜来杀死细菌，同时对哺乳动物细胞保持良性，因为这种损伤模式作用于细菌膜，而不是像传统抗生素那样针对生物合成途径。细菌极难产生耐药菌株，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应用潜力，此外，可环境降解的纳米抗生素有助于解决这一问题。自然栖息地中抗生素废物持续积累的长期问题，改变了敏感生态系统中微生物群落的结构和功能，威胁粮食和水安全，并加速了耐药性的发展，可环境降解的纳米抗生素的发展可能是代表。寻找新抗生素的里程碑，可能具有对抗耐药细菌感染的商业化潜力。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查进行评估，被认为值得支持标准。