Bactericidal antibiotic for Vancomycin Resistant Enterococci

针对万古霉素耐药肠球菌的杀菌抗生素

• 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
• 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' 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

 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很少或根本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生存的能力。肠球菌通常能在致死浓度的抗生素中存活，引起与显着发病率、死亡率和成本相关的感染。我们创建了一系列新型酰基缩肽 (ADEP) 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。当对一组 VRE 临床分离株进行针对这些新抗菌药物的测试时，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，正如对新作用机制所预期的那样。这些化合物对 VRE 的稳定期和生物膜具有强效杀菌作用，但由于 ClpP 蛋白酶的无效突变而出现体外耐药性。知道这些抗菌药物克服耐药性的潜力，我们将它们与传统抗生素结合使用，并且没有检测到耐药性。 ClpP 无效突变体表现出生长缓慢、热敏感性、对许多抗生素的敏感性增加并且在体内无毒力。我们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 和功效进行详细的体外和体内验证，以便从我们专有的 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，我们将能够很好地合作开发该技术，从而进行该药物的 IND 和临床试验。