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: 10460598
• 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/10460598
• 关键词: Acute; Address; Anaerobic Bacteria; Animal Model; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Bacillus; 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; 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.

艰难梭状芽胞杆菌是一种革兰氏阳性，形成孢子的厌氧和产生毒素的芽孢杆菌。这是最大的 医院抗生素相关腹泻的常见原因和假膜共同的病因学因素 疾病预防控制中心在2015年报告 艰难梭菌感染（CDI）的易感性是抗生素对肠道菌群的破坏。第一线 治疗CDI的治疗是口服甲硝唑或万古霉素。这些都不是完全有效的，并且 治疗后，估计感染了艰难梭菌缓解的患者中有15-35％。最近批准的Fidax- Omicin在预防复发方面提高了效率，但其高成本排除了其常规使用。因此，小说 迫切需要低成本和高效率的抗生素以解决令人震惊的CDI流行病。 我们最近开发了一系列新系列可生物降解的聚合物生物材料 - 聚碳酸酯。这些pol- Ymers含有疏水和阳离子基团，模拟宿主防御肽（HDP）并杀死细菌 通过破坏细菌中值膜。重要的是，这些聚合物可以口服并放射 高效率的小鼠艰难梭菌感染，甚至优于万古霉素。此外，这些聚合物 对革兰氏阴性细菌没有活性 肠道微生物，例如大肠杆菌。据我们所知，这是可生物降解的第一个例子 迄今为止，具有针对艰难梭菌的口服生物利用度的聚合物。与万古霉素相比，这些聚合物很容易 大规模合成的成本非常低，并且对优化具有很高的修正，使其非常合成 用于针对艰难梭菌的抗生素治疗。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。该项目的目的是进一步发展这些生物座 通过优化具有更大效力的可分级聚合物。因此，根据我们的初步结果，我们将 首次设计并合成新一代的聚碳酸酯衍生物，具有优化的疏水性和 可以以更高的效力和选择性杀死艰难梭菌的阳离子组。在此之后，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 <0.5 µg/mL，选择性指数（SI）：HC50/MICC.Difficile> 2000，用于血细胞，IC50/MICC.Difficile> 250用于Mamma- Lian细胞）将进一步探索其作用机理。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。 我们的项目很重要，因为我们正在解决重要的细菌菌株艰难梭菌的感染， 我们正在开发新型的聚合生物材料。我们还认为我们的项目具有创新性，因为我们正在 循环一类新的可生物降解和口服的多碳酸盐，它们已经显示 可以轻松和选择性，并且可以大规模合成以低成本的综合。结果，新一代 与艰难梭菌作斗争的抗生素剂将由我们的项目产生。