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

这个I-Corps项目的更广泛的影响/商业潜力是开发抗生素以减轻多重耐药细菌感染。抗生素耐药性是一个全球性的公共卫生危机，根据CDC的说法，它是“我们最严重的健康威胁之一”。世界已经见证了超级细菌的激增，它们以惊人的速度逃避一种或多种抗生素。这种情况由于缺乏新的抗生素而加剧，并且人工抗生素废物在自然栖息地的积累越来越多，进一步加速了耐药基因组的发展。膜活性抗菌剂（MAA）已被广泛预期为新抗生素的有希望的候选者。然而，毒性是将MAA转化为市场的最大障碍之一，其中破坏细菌和哺乳动物膜的不加选择的疏水相互作用是一个主要因素。 该技术使用亲水性纳米抗生素，可以高效杀死细菌，包括多药耐药（MDR）菌株，而不会损害哺乳动物细胞。 此外，它们在作为废物排放时，会被自然生境中的酶迅速降解和钝化。 这项技术可能被用来解决抗生素耐药性的危机。这个I-Corps项目是基于生物相容性和环境友好的纳米抗生素的发展。所提出的技术已经证明，组装成纳米结构的聚合物分子刷（PMBs）的亲水性和抗微生物非活性的线性链聚合物打开“ON”他们的抗微生物活性集体，而拆卸的纳米结构的PMBs打开所获得的活动“OFF”。此外，纳米抗生素已被证明可以通过选择性地破坏细菌膜来杀死细菌，同时对哺乳动物细胞保持良性。由于这种损伤模式作用于细菌膜，而不是像传统抗生素那样靶向生物合成途径，因此细菌极难产生耐药菌株。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应用潜力。 此外，可环境降解的纳米抗生素有助于解决长期存在的抗生素废物在自然栖息地中持续积累的问题，这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，并加速了耐药基因组的发展。 环境可降解纳米抗生素的开发可能是寻找新抗生素的一个里程碑，并可能具有商业化潜力，以对抗耐药细菌感染。该奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的知识价值和更广泛的影响审查标准进行评估的支持。

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.