Novel antibacterials targeting the 50S ribosomal subunit

描述(由申请人提供)：这项提案的具体目标是在确定一种化合物(S)可以商业化并开出处方用于治疗耐多药革兰氏阳性医院获得性感染后，启动临床前研究，以满足调查性新药申请(IND)的要求。关键病原体中多药耐药频率的增加促使我们采用基于结构的设计方法来识别针对多药耐药(MDR)革兰氏阳性病原体的化合物。对于由革兰氏阳性病原体引起的医院感染，药物必须包括金黄色葡萄球菌、表皮葡萄球菌、粪肠球菌和粪肠球菌。肺炎链球菌(用于治疗因社区获得性肺炎住院或在住院期间发展为革兰氏阳性肺炎的患者)和其他种类的葡萄球菌和肠球菌将是非常可取的。为了在商业上取得成功，该药物的药代动力学与每天一到两次的剂量相称是非常可取的。对于医院内危及生命的感染，需要静脉注射剂，最好是口服相同药物的制剂。展望未来，该药物将覆盖对大环内酯类、喹诺酮类、万古霉素、β-内酰胺类、赛诺西德和利奈唑胺具有耐药性的菌株。 在我们的第一阶段应用中，我们开始识别一种抑制细菌细胞中蛋白质合成的新化学实体的活性核心，确定其与其目标(核糖体的SOS亚基)络合时的3D结构，并确定这一系列中一种化合物的基本药代动力学。在成功完成我们第一阶段申请的所有目标后，我们在第二阶段提案中寻求： 1.在我们的初级小组中，测定MIC=5g/ml的化合物对革兰氏阳性病原体的MIC90值。 2.在相关动物感染模型上测定疗效。 3.表征化合物可能引起的药物相互作用、不良副作用、微粒体失稳、细胞毒性，以及它们具有口服吸收的潜力。 4.研究化合物在啮齿动物和非啮齿动物体内的药代动力学特征。 5.确定关键化合物产生抗药性的速度。 6.启动一种化合物的临床前研究，该化合物符合治疗医院内革兰氏阳性菌的可接受标准。 预计这些工作单位将在IND对一种有效对抗革兰氏阳性医院病原体的化合物进行备案方面取得实质性进展。

DESCRIPTION (provided by applicant): The specific goal of this proposal is to initiate preclinical studies towards satisfying the requirements for an Investigative New Drug Application (IND) after identifying a compound(s) that could be commercialized and prescribed for the treatment of multidrug-resistant (MDR) Gram-positive hospital-acquired infections. The increased frequency of multidrug resistance in key pathogens has motivated us to employ our structure-based design approach to identify compounds that target multidrug-resistant (MDR) Gram-positive pathogens. For use in nosocomial infections caused by Gram-positive pathogens, a drug must cover Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, and Enterococcus faecium. Coverage of Streptococcus pneumonias (for treatment of patients who are either hospitalized due to community-acquired pneumonia or develop a Gram-positive pneumonia while hospitalized) and other species of staphylococci and enterococci would be highly desirable. To be commercially successful, it would be highly desirable for the drug to have pharmacokinetics commensurate with once or twice daily dosing. For life-threatening infections in the hospital, an IV agent would be needed, ideally followed by an oral formulation of the same drug. Looking ahead, this agent would cover strains that have resistance to macrolides, quinolones, vancomycin, ¿-lactams, Synercid(r), and Linezolid. In our Phase I application, we set out to identify the active core of a new chemical entity that inhibits protein synthesis in the bacterial cell, determine its 3D structure when complexed to its target (the SOS subunit of the ribosome), and determine basic pharmacokinetics of one compound in this promising series. Having successfully completed all the goals from our Phase I application, we seek in this Phase II proposal to: 1. Determine MIC90 values for compounds with MICs = 5 ¿g/ml against Gram-positive pathogens in our primary panel. 2. Determine efficacy in relevant animal models of infection. 3. Characterize compounds for potential to cause drug-drug interactions, adverse side-effects, microsomal lability, cytotoxicity, and for their potential to have oral absorption. 4. Characterize the pharmacokinetic profile of compounds in rodent and non-rodent species. 5. Determine how quickly resistance occurs with key compounds. 6. Initiate preclinical studies on a compound that meets acceptable criteria for treatment of nosocomial Gram-positive bacteria. It is expected that these units of work will provide substantial progress toward an IND filing of a compound active against Gram-positive nosocomial pathogens.