Bactericidal antibiotic for Vancomycin Resistant Enterococci

 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）的治疗药物。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没有有效的治疗选择的地步。对于肠球菌而言，耐药性与病原体在杀菌抗生素存在下的耐受性和存活能力内在地联系在一起。肠球菌在通常致死浓度的抗生素中存活，引起与显著的发病率、死亡率和成本相关的感染。我们已经创造了一系列新的酰基缩酚酸肽（ADEP）抗菌剂，这些抗菌剂激活ClpP蛋白酶，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检测时，未检测到与用于治疗该病原体的抗生素的交叉耐药性，这与新型作用机制的预期一致。这些化合物对VRE的固定相和生物膜具有强效杀菌作用，然而由于ClpP蛋白酶中的无效突变而发生体外抗性。了解到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，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）和其他重要性质。我们将对VRE的安全性、PK和疗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。一旦得到验证，我们将能够很好地与该技术合作进行开发，从而导致该药物的IND和临床试验。

 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.