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

基本信息

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
项目类别：
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

项目摘要

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且新兴的全球医疗保健问题。 B-LACTAM抗生素是现代医学中最重要的发展之一，已挽救了数百万的生命，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效率的关键结构。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抗性。 B-内酰胺的产量和Extreme是多种耐药细菌病原体采用的主要防御机制。例如，几乎30％的医院获得感染被确定为耐甲氧西林金黄色葡萄球菌（MRSA）菌株，这些菌株对青霉素，甲氧西林和许多其他β-内酰胺抗生素具有抗性，导致患者严重感染问题。目前，万古霉素和阿莫西林/克拉素酸是治疗革兰氏阳性细菌感染的最常用抗生素之一。尽管这些抗生素是其类别的强项，但高频使用导致其易感性下降。有效的抗生素和/或抗菌剂的需求量很高，但在抵抗细菌耐药性方面的成功有限。我们发现了一类带电的金属聚合物，该金属聚合物通过有效裂解细菌细胞并有效解除β-内酰胺酶的活性来表现出针对多药抗性细菌的协同作用。各种常规的β-内酰胺抗生素，包括青霉素-G，阿莫西林，阿莫西林和头孢唑素，都可以通过β-内酰胺酶水解保护它们的羧酸盐阴离子和阳离子金属聚合物之间的独特离子对形成。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地防止细菌抗性；（2）更重要的是，我们的金属聚合物平台消除了通过解除β-乳糖苷酶并破坏细胞膜的抗药性复发的可能性；（3）这些金属聚合物对于哺乳动物细胞是非或微小的细胞毒性。我们的研究和发现可以为设计大分子支架的新途径提供新的途径，以再生常规抗生素的生命力，以杀死多药耐药细菌和超级细菌。