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

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.