Metallopolymer and Antibiotic Bioconjugates against Multidrug Resistant Bacteria

针对多重耐药细菌的金属聚合物和抗生素生物共轭物

• 批准号: 9001064
• 负责人: Chuanbing Tang
• 金额: $ 36.16万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-11-01 至 2019-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9001064
• 关键词: Acylation; Address; Adsorption; Advanced Development; Amino Acids; Amoxicillin; Amoxicillin-Potassium Clavulanate Combination; Ampicillin; Anions; Antibiotic Therapy; Antibiotics; Bacteria; Bacterial Infections; Bacterial Typing; Cefazolin; Cell Culture Techniques; Cell Wall; Cell membrane; Cell surface; Cells; Cessation of life; Charge; Clinical; Communicable Diseases; Complex; Cytolysis; Defense Mechanisms; Development; Drug resistance; Enzymes; Eukaryotic Cell; Excretory function; Exhibits; Frequencies; Goals; Gram-Positive Bacterial Infections; Health Care Costs; Healthcare; Human; Hydrolysis; In Vitro; Infection; Ions; Lactamase; Lead; Mammalian Cell; Metabolism; Metals; Methicillin; Methods; Microbiology; Modern Medicine; Monobactams; Morbidity - disease rate; Multi-Drug Resistance; Mus; Natural regeneration; Nosocomial Infections; Pathway interactions; Patients; Penicillin G; Penicillin Resistance; Polymer Chemistry; Polymers; Predisposition; Production; Recurrence; Research; Residual state; Resistance development; Role; Structure; Superbug; System; Techniques; Testing; Tissues; Toxic effect; Vancomycin; Work; X-Ray Crystallography; absorption; antimicrobial; antimicrobial drug; antimicrobial peptide; bacterial resistance; base; beta-Lactamase; beta-Lactams; carboxylate; cytotoxic; deacylation; design; disability; fighting; in vivo; innovation; killings; metal poisoning; methicillin resistant Staphylococcus aureus; novel; pathogen; prevent; public health relevance; scaffold; structural biology; success; systemic toxicity

 DESCRIPTION: Bacterial Infections are an important and emerging global healthcare issue. Β-Lactam antibiotics, one of the most important developments in modern medicine, have saved millions of lives and continue to serve as the major therapy to treat bacterial infections. The highly reactive four- membered β-lactam ring is the key structure for dictating efficacy of this class of antibiotics. Unfortunately, bacteria are rapidly developing resistance to one or more of the most frequently used antibiotics. Β-Lactamase production and excretion is a major defense mechanism employed by several drug-resistant bacterial pathogens. For example, nearly 30% of hospital- acquired infections are identified as methicillin-resistant Staphylococcus aureus (MRSA) strains that are resistant to penicillin, methicillin and many other β-lactam antibiotics, leading to serious infection problems for patients. Currently, vancomycin and amoxicillin/clavulanic acid are among the most commonly used antibiotics for the treatment of Gram-positive bacterial infections. Although these antibiotics are among the strongest of their classes, the high frequency use has resulted in their decreased susceptibility. Efficient antibiotics and/or antimicrobial agents are in high demand, but have limited success in fighting bacterial resistance. We discover a class of charged metallopolymers that exhibits synergistic effects against multidrug resistant bacteria by effectively lysing bacterial cells and efficiently disarming activity of β-lactamases. Various conventional β-lactam antibiotics, including penicillin-G, amoxicillin, ampicillin and cefazolin, are protected from β-lactamase hydrolysis via the formation of unique ion-pairs between their carboxylate anions and cationic metallopolymers. There are at least three innovations involved in this project: (1) our approaches effectively prevent bacterial resistance by protecting and reinstating antibiotics; (2) more importantly our metallopolymer platforms eliminate the possibility of recurrence of bacterial resistance via disarming β- lactamases and disrupting cell membranes; (3) these metallopolymers are non- or minimally cytotoxic for mammalian cells. Our research and discoveries could provide a new pathway to designing macromolecular scaffolds to regenerate vitality of conventional antibiotics to kill multidrug resistant bacteria and superbugs.

 描述：细菌感染是一个重要的和新兴的全球医疗保健问题。Β-内酰胺抗生素是现代医学最重要的发展之一，已经挽救了数百万人的生命，并继续作为治疗细菌感染的主要疗法。高反应性的四元β-内酰胺环是决定这类抗生素功效的关键结构。不幸的是，细菌正在迅速发展对一种或多种最常用的抗生素的耐药性。Β-内酰胺酶的产生和分泌是几种耐药细菌病原体采用的主要防御机制。例如，近30%的医院获得性感染被鉴定为耐甲氧西林金黄色葡萄球菌（MRSA）菌株，其对青霉素、甲氧西林和许多其他β-内酰胺抗生素具有抗性，导致患者的严重感染问题。目前，万古霉素和阿莫西林/克拉维酸是治疗革兰氏阳性细菌感染最常用的抗生素。虽然这些抗生素是同类抗生素中最强的，但高频率使用导致其敏感性降低。高效的抗生素和/或抗微生物剂的需求很高，但在对抗细菌耐药性方面的成功有限。我们发现了一类带电荷的金属聚合物，其通过有效地裂解细菌细胞和有效地解除β-内酰胺酶的活性而对多重耐药细菌表现出协同作用。各种常规的β-内酰胺抗生素，包括青霉素-G、阿莫西林、氨苄西林和头孢唑啉，通过以下途径被保护免于β-内酰胺酶水解： 它们的羧酸根阴离子和阳离子金属聚合物之间形成独特的离子对。该项目至少涉及三项创新：（1）我们的方法通过保护和恢复抗生素有效预防细菌耐药性;（2）更重要的是，我们的金属聚合物平台通过解除β-内酰胺酶和破坏细胞膜消除了细菌耐药性复发的可能性;（3）这些金属聚合物对哺乳动物细胞无细胞毒性或细胞毒性极小。我们的研究和发现可以提供一种新的途径来设计大分子支架，以再生传统抗生素的活力，从而杀死多重耐药细菌和超级细菌。