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

基本信息

批准号：
10023161
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
项目类别：
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/10023161
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 combat cost cytotoxicity design gut microbiota improved indexing innovation microbial mouse model novel pathogenic bacteria polycarbonate prevent sound

项目摘要

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、产毒的杆菌。院内抗生素相关性腹泻的常见原因及伪膜性腹泻的病因据 CDC 2015 年报告，美国每年约有 453,000 例病例和 29,000 例死亡。艰难梭菌感染 (CDI) 的易感性是抗生素对肠道微生物群的破坏。治疗 CDI 的疗法是口服甲硝唑或万古霉素，这些药物均不完全有效，并且是一种有效的治疗方法。估计 15-35% 的艰难梭菌感染者在接受最近批准的 fidax-治疗后会复发。 omicin 可以提高预防复发的功效，但其成本较高，因此无法常规使用。迫切需要低成本、高效的抗生素药物来应对令人震惊的 CDI 疫情。我们最近开发了一系列新的可生物降解高分子生物材料——聚碳酸酯。 ymer 含有疏水基团和阳离子基团，可模拟宿主防御肽 (HDP) 并杀死细菌重要的是，这些聚合物可以通过口服给药并根除。对小鼠感染艰难梭菌的疗效甚至优于万古霉素。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据我们所知，这是第一个可生物降解的例子。迄今为止，与万古霉素相比，这些聚合物具有针对艰难梭菌的口服生物利用度。以非常低的成本进行大规模合成，并且高度易于优化，使它们非常有前景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抗生素治疗。该项目的目标是进一步开发这些生物降解药物。因此，根据我们的初步结果，我们将通过优化获得具有更大效力的可分级聚合物。首次设计并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随后，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。（MIC < 0.5 µg/mL，选择指数 (SI)：血细胞 HC50/MICC.difficile > 2000，哺乳动物 IC50/MICC.difficile > 250 随后，我们还将进一步探讨其治疗作用。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）中的功效。我们的项目意义重大，因为我们正在解决重要菌株艰难梭菌的感染，我们正在开发新型聚合物生物材料，我们也相信我们的项目是创新的，因为我们正在开发。开发出一类新的可生物降解且可口服的聚碳酸酯，它已经显示出显着的效果：具有高效性和选择性，并且可以以低成本大规模合成，从而产生新一代。我们的项目将产生对抗艰难梭菌的抗生素药物。