Bactericidal antibiotic for Vancomycin Resistant Enterococci

针对万古霉素耐药肠球菌的杀菌抗生素

基本信息

批准号：
9243208
负责人：
Michael LaFleur
金额：
$ 125.16万
依托单位：
ARIETIS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-15 至 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9243208
关键词：
Agar Aminoglycosides Anti-Infective Agents Antibiotic Resistance Antibiotics Antimicrobial Resistance Area Under Curve Autopsy Back Bacteria Binding Proteins Biochemical Biological Assay Biophysics Body Weight Caco-2 Cells Cardiovascular system Cell Death Cell Wall Cells Clinical Clinical Data Clinical Trials Clinical Trials Design Collaborations Crystallization Data Development Devices Dose Drug Kinetics Drug Tolerance Endocarditis Enterococcus Enterococcus faecalis Enterococcus faecium Enzyme Inhibition Exhibits Fiber Goals Growth Half-Life Health Heart Hepatocyte Hormonal In Vitro Infection Intestinal Absorption Kidney Lead Left Link Liver Lung Maximum Tolerated Dose Measurement Microbial Biofilms Microbiology Mitochondria Modeling Morbidity - disease rate Mus Penicillins Peptide Hydrolases Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Phase Plasma Positioning Attribute Predisposition Property Rattus Resistance Resistance development Resort Rifampin Safety Saint Jude Children&apos s Research Hospital Septicemia Series Solubility Specialist Staphylococcus aureus Streptomycin Structure Testing Therapeutic Thigh structure Time Tissue Cage Tissues Validation Vancomycin Vancomycin resistant enterococcus analog antimicrobial antimicrobial drug attributable mortality bactericide base beta-Lactams chemical property chemical stability cost cytotoxicity design effective therapy experimental study genotoxicity improved in vivo killings methicillin resistant Staphylococcus aureus mortality mutant novel novel therapeutics null mutation pathogen physical property pre-clinical preclinical development protein degradation public health relevance receptor resistance frequency resistance mechanism resistant strain response technology development tigecycline vancomycin B

项目摘要

DESCRIPTION (provided by applicant): The goal of the project is to develop a therapeutic against vancomycin resistant enterococcus (VRE). These infections are a serious health concern because antibiotic resistance has gotten to the point where there are few or no effective treatment options available. For the enterococci, resistance is inherently linked to tolerance - th ability of the pathogen to survive in the presence of bactericidal antibiotics. The enterococci survive typically lethal concentrations of antibiotics, causing an infection associated with significant morbidity, mortality and costs. We have created a novel series of acyldepsipeptide (ADEP) antimicrobials that activate the ClpP protease, which leads to protein degradation, overcoming drug tolerance and resulting in cell death. When a panel of VRE clinical isolates was tested against these new antimicrobials, no cross resistance with antibiotics used to treat this pathogen was detected, as expected for a novel mechanism of action. The compounds were potently bactericidal against stationary phase and biofilms of VRE, however in vitro resistance occurred due to null mutations in the ClpP protease. Knowing the potential of these antimicrobials to overcome drug tolerance, we combined them with traditional antibiotics and did not detect resistance. ClpP null mutants exhibit slow growth, heat sensitivity, increased susceptibility to many antibiotics and are avirulent in vivo. We have optimized the pharmacokinetics (PK) and other important properties of the series. We will perform detailed in vitro and in vivo validation of safety, PK, and efficacy against VRE in order to identify a pre-clinical lead and suitable backup candidate from among our proprietary series of ADEP analogs. Once validated, we will be well positioned to partner the technology for development, leading to an IND and clinical trials of the drug.

描述（由适用提供）：该项目的目的是开发针对万古霉素耐药肠球菌（VRE）的治疗性。这些感染是一个严重的健康问题，因为抗生素耐药性已达到几乎没有或没有有效治疗方案的地步。对于肠球菌，抗性与耐受性 - 病原体在存在细菌抗生素存在下生存的能力。肠球菌的生存通常是致命的抗生素浓度，导致与大量发病率，死亡率和成本相关的感染。我们创建了一系列新型的Ayldepsipeptide（EDEP）抗菌剂，该抗菌激活CLPP蛋白，从而导致蛋白质降解，克服药物耐受性并导致细胞死亡。当针对这些新的抗菌剂测试了一组VRE临床分离株时，没有检测到用于治疗该病原体的抗生素的交叉耐药性，这是一种新型作用机理所预期的。这些化合物是VRE的潜在生物学阶段和生物膜，但是由于CLPP蛋白酶中的无突变，体外耐药性发生。了解这些抗菌剂克服药物耐受性的潜力，我们将它们与传统的抗生素结合在一起，没有检测到抗药性。 CLPP无效突变体暴露了缓慢的生长，热敏性，对许多抗生素的敏感性增加，并且在体内无动于衷。我们已经优化了该系列的药代动力学（PK）和其他重要特性。我们将对VRE的安全性，PK和效率进行详细的体外和体内验证，以确定我们专有的一系列EDEP类似物中的临床前铅和合适的备份候选者。一旦得到验证，我们将有能力合作开发技术，从而导致该药物的IND和临床试验。