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（由申请人提供）：该项目的目标是开发一种针对万古霉素耐药肠球菌（VRE）的治疗方法。这些感染是一个严重的健康问题，因为抗生素耐药性已经达到了几乎没有或没有有效治疗选择的程度。对于肠球菌来说，耐药性本质上与耐受性相关，即病原体在杀菌抗生素存在下存活的能力，肠球菌通常能在致死浓度的抗生素中存活，从而引起与显着相关的感染。我们创建了一系列新型酰基缩肽 (ADEP) 抗菌剂，当对一组 VRE 临床分离株进行测试时，该抗菌剂可激活 ClpP 蛋白酶，从而导致蛋白质降解，克服药物耐受性并导致细胞死亡。新的抗菌剂，没有检测到与用于治疗这种病原体的抗生素的交叉耐药性，正如预期的新作用机制一样，这些化合物对固定相和生物膜具有有效的杀菌作用。然而，体外耐药性是由于 ClpP 蛋白酶的无效突变而发生的，我们知道这些抗菌剂具有克服耐药性的潜力，因此将它们与传统抗生素结合使用，并且没有检测到 ClpP 无效突变体表现出生长缓慢、热敏感性增加。对许多抗生素敏感，并且体内无毒。我们已经优化了该系列的药代动力学（PK）和其他重要特性，我们将对其安全性、PK 和功效进行详细的体外和体内验证。 VRE 旨在从我们专有的 ADEP 类似物系列中确定临床前先导药物和合适的备用候选药物。一旦经过验证，我们将能够与该技术合作进行开发，从而进行该药物的 IND 和临床试验。