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治疗万古霉素耐药肠球菌(VRE)。这些感染是一个严重的健康问题，因为抗生素耐药性已经到了几乎没有有效治疗选择的地步。对于肠球菌来说，耐药性与耐受性有关--病原体在杀菌抗生素存在的情况下生存的能力。肠球菌在典型的致死浓度的抗生素下存活，导致与显著的发病率、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二肽类(ADEP)抗菌剂，这些抗菌剂可以激活ClpP蛋白酶，导致蛋白质降解，克服药物耐药性，导致细胞死亡。当一组VRE临床分离株对这些新的抗菌素进行测试时，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，这是一种新的作用机制所预期的。这些化合物对VRE的固定相和生物膜具有有效的杀菌作用，但由于ClpP蛋白酶的零突变而在体外产生耐药性。了解到这些抗菌药克服耐药性的潜力，我们将它们与传统抗生素结合，没有检测到耐药性。ClpP缺失突变体具有生长缓慢、热敏感、对多种抗生素敏感性高、体内无毒等特点。我们优化了该系列的药代动力学(PK)和其他重要性质。我们将在体外和体内对VRE进行详细的安全性、PK和有效性验证，以便从我们专有的ADEP类似物系列中确定临床前领先和合适的备用候选药物。一旦得到验证，我们将很好地与这项技术合作进行开发，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.