Novel polymer biomaterials combating C. difficile infection

艰难梭菌是一种革兰氏阳性、芽胞形成、厌氧和产毒素的杆菌。它是最多的 医院内抗生素相关性腹泻常见原因及伪膜性肠炎的病原学研究 据美国疾病控制与预防中心2015年报告，美国每年约有453,000例利蒂炎病例和29,000人死亡。中心到 艰难梭菌感染(CDI)的易感性是抗生素破坏肠道微生物区系。第一线 治疗CDI的方法是口服甲硝唑或万古霉素。所有这些都不是完全有效的，而且 据估计，感染艰难梭菌的人中有15%-35%在治疗后复发。最近批准的fidax- 奥米星在预防复发方面效果更好，但其高昂的成本阻碍了其常规使用。因此，小说 迫切需要低成本、高效率的抗生素来应对令人震惊的CDI疫情。 我们最近开发了一系列新的可生物降解的聚合物生物材料-聚碳酸酯。这些波兰人- 同时含有疏水基团和阳离子基团的聚合物可以模拟宿主防御肽(HDPs)并杀死细菌 通过破坏细菌的细胞膜。重要的是，这些聚合物可以口服并清除 对小鼠感染艰难梭菌的疗效高，甚至优于万古霉素。此外，这些聚合物 对革兰氏阴性菌没有活性，因此它们不会破坏共生的革兰氏阴性菌 肠道微生物，如大肠杆菌。据我们所知，这是第一个可生物降解的例子 到目前为止，具有口服生物利用度的聚合物抗艰难梭菌。与万古霉素相比，这些聚合物更容易 以极低的成本大规模合成，并高度可优化修改，使它们非常容易- 对艰难梭菌进行抗生素治疗。我们的长期目标是开发可生物降解的聚碳酸酯作为 针对艰难梭菌的新一代抗生素。该项目的目标是进一步开发这些生物降解技术。 通过优化使可分级聚合物具有更大的效力。因此，根据我们的初步结果，我们将 首次设计合成新一代聚碳酸酯衍生物，具有优化的疏水性和 能够以更高的效力和选择性杀死艰难梭菌的阳离子基团。之后，我们将确定 新设计的聚合物对艰难梭菌的抗菌活性和选择性。最有效的聚合物 (MIC&lt；0.5微克/毫升，选择指数(SI)：血细胞：HC50/MICC.fficile&gt；2000，母亲IC50/MICC.fficile&gt；250- 连氏细胞)的作用机制将被进一步研究。随后，我们还将评估治疗效果 这些最有效的聚碳酸酯在CDI动物模型(小鼠模型和急性仓鼠模型)中的有效性。 我们的项目意义重大，因为我们正在应对重要细菌艰难梭菌的感染， 我们正在开发新型的聚合物生物材料。我们也相信我们的项目是创新的，因为我们正在 开发一种新的可生物降解和口服的聚碳酸酯，已经表明- 具有良好的药效和选择性，可以低成本大规模合成。因此，新一代 我们的项目将产生对抗艰难梭菌的抗生素。

Clostridium difficile is a Gram-positive, spore-forming anaerobic and toxin-producing bacillus. It is the most common cause of nosocomial antibiotic-associated diarrhea and the etiologic agent of pseudomembranous co- litis with about 453,000 cases and 29,000 deaths yearly in the U.S. as reported by CDC in 2015. Central to predisposition to C. difficile infection (CDI) is the disruption of the gut microbiota by antibiotics. The first-line therapy for the treatment of CDI is oral metronidazole or vancomycin. None of these is fully effective, and an estimated 15-35% of those infected with C. difficile relapse following treatment. The recently approved fidax- omicin has improved efficacy in preventing recurrence, but its high cost precludes its routine use. As such, novel antibiotic agents with low cost and high efficacy are desperately needed to address the alarming CDI epidemic. We recently have developed a new series of biodegradable polymer biomaterials-polycarbonates. These pol- ymers, containing both hydrophobic and cationic groups, mimic host-defense peptides (HDPs) and kill bacteria through disruption of bacterial membranes. Importantly, these polymers can be orally administered and eradicate C. difficile infection in mice with high efficacy which is even superior to vancomycin. Furthermore, these polymers are not active against Gram-negative bacteria, and therefore they do not destroy commensal Gram-negative intestinal microbes such as E. coli. To the best of our knowledge, this is the first example of biodegradable polymers with oral bioavailability against C. difficile to date. Compared to vancomycin, these polymers are easy to synthesize in a large scale with very low cost, and highly amendable to optimization, making them very prom- ising for antibiotic therapy against C. difficile. Our long-term goal is to develop biodegradable polycarbonates as new generation of antibiotics against C. difficile. The objective of this project is to further develop these biode- gradable polymers with greater potency through optimization. As such, based on our preliminary results, we will first design and synthesize new generation of polycarbonate derivatives bearing optimized hydrophobic and cationic groups that can kill C. difficile with higher potency and selectivity. Following that, we will determine antibacterial activity and selectivity of the newly designed polymers against C. difficile. The most potent polymers (MIC < 0.5 µg/mL, Selective Index (SI): HC50/MICC.difficile > 2000 for blood cells, IC50/MICC.difficile > 250 for mamma- lian cells) will be further explored for their mechanism of action. Subsequently, we will also evaluate therapeutic efficacy of these most potent polycarbonates in animal models (mouse model and acute hamster model) of CDI. Our project is significant, because we are tackling the infection from the significant bacterial strain C. difficile, and we are developing novel polymeric biomaterials. We also believe our project is innovative, as we are de- veloping a new class of biodegradable and orally available polycarbonates, which have already showed remark- able efficacy and selectivity, and could be synthesized in large scale with low cost. As a result, a new generation of antibiotic agents combating C. difficile will be resulted from our project.