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来减轻多重耐药细菌感染。根据疾控中心的说法，抗生素耐药性是一种全球公共卫生危机，也是“我们最严重的健康威胁之一”。世界上已经见证了超级细菌的激增，它们以惊人的速度避开了一种或多种抗生素。由于缺乏新的抗生素，以及人工抗生素废物在自然栖息地积累的增加，进一步加速了耐药性的发展，这种情况加剧了这种情况。膜活性抗菌剂(MAAs)被广泛认为是新型抗生素的候选药物。然而，毒性是MAAS推向市场的最大障碍之一，其中破坏细菌和哺乳动物细胞膜的不分青红皂白的疏水相互作用是一个主要因素。这项拟议的技术使用亲水性纳米抗生素，在不损害哺乳动物细胞的情况下高效地杀死细菌，包括多药耐药(MDR)细菌菌株。此外，它们已被证明在作为废物释放时会被自然栖息地中存在的酶快速降解和失活。这项技术可能会被用来解决抗生素耐药性的危机。这个i-Corps项目是基于生物兼容和环境友好的纳米抗生素的开发。这项拟议的技术已经证明，将亲水性和抗菌性不活跃的直链聚合物组装成纳米结构聚合物分子刷(PMB)，可以共同打开它们的抗菌活性，而拆解纳米结构PMB会关闭获得的活性。此外，纳米抗生素已被证明通过选择性地破坏细菌膜而杀死细菌，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膜，而不是像传统抗生素那样针对生物合成途径，因此细菌产生耐药菌株是极其困难的。纳米抗生素对哺乳动物细胞的低毒性进一步表明其具有很大的临床应用潜力。此外，环境可降解的纳米抗生素有助于解决抗生素废物在自然生境中持续积累的长期问题，这会改变敏感生态系统中微生物群落的结构和功能，威胁食品和水安全，并加速耐药性的发展。环境可降解纳米抗生素的开发可能代表着寻找新抗生素的里程碑，并可能具有对抗耐药细菌感染的商业潜力。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.