Novel polymer biomaterials combating C. difficile infection

对抗艰难梭菌感染的新型聚合物生物材料

• 批准号: 9907591
• 负责人: Jianfeng Cai
• 金额: $ 37.38万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-23 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9907591
• 关键词: Acute; Address; Anaerobic Bacteria; Animal Model; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacillus (bacterium); Bacteria; Biocompatible Materials; Biological Availability; Blood Cells; Cations; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clostridium difficile; Development; Epidemic; Escherichia coli; Etiology; Foundations; Generations; Goals; Gram-Negative Bacteria; Hamsters; Host Defense; Hydrophobicity; Infection; Intestines; Lead; Light; Literature; Mammalian Cell; Membrane; Metronidazole; Modeling; Modification; Mus; Oral; Peptides; Polymers; Predisposition; Pseudomembranous Colitis; Publishing; Recurrence; Relapse; Reporting; Reproduction spores; Research; Resistance; Resistance development; Risk Factors; Series; Testing; Toxin; Treatment Efficacy; Ursidae Family; Vancomycin; Work; antibiotic-associated diarrhea; antimicrobial drug; base; biodegradable polymer; combat; cost; cytotoxicity; design; gut microbiota; improved; indexing; innovation; microbial; mouse model; novel; pathogenic bacteria; polycarbonate; prevent; sound

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.

艰难梭菌是一种革兰氏阳性、产芽孢、厌氧和产毒素的芽孢杆菌。它是最 医院感染相关性腹泻的常见原因和伪膜性腹泻的病原体 据CDC在2015年报道，美国每年约有453，000例病例和29，000例死亡。的核心 倾向于C.艰难梭菌感染（CDI）是抗生素对肠道微生物群的破坏。一线 治疗CDI的疗法是口服甲硝唑或万古霉素。这些都不是完全有效的， 估计15-35%的人感染C.治疗后难以复发。最近批准的fidax- omicin在预防复发方面具有改进的功效，但是其高成本排除了其常规使用。因此，小说 迫切需要具有低成本和高功效的抗生素剂来解决令人担忧的CDI流行病。 我们最近开发了一系列新的可生物降解的高分子生物材料-聚碳酸酯。这些警察- 含有疏水基团和阳离子基团的聚合物模拟宿主防御肽（HDPs）并杀死细菌 通过破坏细菌膜。重要的是，这些聚合物可以口服施用并根除 C.对小鼠艰难梭菌感染具有很高的疗效，甚至上级优于万古霉素。此外，这些聚合物 对革兰氏阴性菌没有活性，因此它们不会破坏革兰氏阴性菌的细胞， 肠道微生物如E.杆菌据我们所知，这是第一个可生物降解的 具有口服生物利用度的聚合物。至今为止都很难。与万古霉素相比，这些聚合物 以非常低的成本大规模合成，并且高度可优化，使它们非常prom- 用于抗C.很难我们的长期目标是开发可生物降解的聚碳酸酯， 新一代抗C.很难该项目的目标是进一步开发这些生物- 通过优化使聚合物具有更大的效力。因此，根据初步结果，我们将 首次设计合成了新一代聚碳酸酯衍生物， 阳离子基团可以杀死C.具有更高的效力和选择性。在此之后，我们将确定 抗菌活性和选择性的新设计的聚合物对C。很难最有效的聚合物 (MIC< 0.5 µg/mL，选择性指数（SI）：血细胞的HC 50/MICC.difficile > 2000，乳腺癌的IC 50/MICC.difficile > 250。 lian细胞）将进一步探索其作用机制。随后，我们还将评估治疗 这些最有效的聚碳酸酯在CDI的动物模型（小鼠模型和急性仓鼠模型）中的功效。 我们的项目意义重大，因为我们正在解决来自重要细菌菌株C的感染。difficile， 我们正在开发新型聚合生物材料。我们也相信我们的项目是创新的，因为我们是德- 公开了一类新的可生物降解的和口服可利用的聚碳酸酯，其已经显示出显著的 具有较好的效果和选择性，可大规模低成本合成。因此，新一代 抗生素对抗C.我们的项目将带来困难。