Novel DNA Polymerase Inhibitors as Gram-Positive Antibacterial Agents

作为革兰氏阳性抗菌剂的新型 DNA 聚合酶抑制剂

• 批准号: 8105156
• 负责人: Thale Cross Jarvis
• 金额: $ 49.69万
• 依托单位: CRESTONE, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-06 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8105156
• 关键词: Acute; Adverse effects; Animals; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Bacillus anthracis; Bacterial DNA; Binding; Biochemical; Biological Assay; Biological Availability; Blood; Cell Culture Techniques; Chemicals; Clinical; Clostridium difficile; Collection; Coupled; DNA Polymerase Inhibitor; DNA biosynthesis; DNA-Directed DNA Polymerase; Data; Development; Dose; Drug Kinetics; Drug resistance; Drug toxicity; Ensure; Enterococcus faecalis; Evaluation; Exhibits; Funding; General Population; Goals; Government; Gram-Positive Bacteria; Health Benefit; Human; In Vitro; Incidence; Infection; Investigational Drugs; Lead; Linezolid; Liver; Liver Microsomes; Mammalian Cell; Marketing; Measures; Metabolic; Microsomes; Modeling; Molecular Target; Mus; Natural Resistance; Oral; Outcome; Pathway interactions; Penicillin Resistance; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Plasma; Plasma Proteins; Population; Property; Protein Binding; Public Health; Rattus; Research; Resistance; Risk Factors; Safety; Schedule; Screening procedure; Series; Serum; Staging; Staphylococcus aureus; Streptococcus pneumoniae; Streptococcus pyogenes; Structure; Structure-Activity Relationship; Testing; Thigh structure; Toxic effect; Uracil; Vancomycin resistant enterococcus; bactericide; base; biothreat; candidate selection; combat; compound 30; cytotoxicity; drug candidate; drug development; drug resistant bacteria; improved; in vivo; inhibitor/antagonist; meetings; methicillin resistant Staphylococcus aureus; novel; pathogen; physical property; pre-clinical; process optimization; programs; receptor; receptor binding; response

DESCRIPTION (provided by applicant): The alarming increase in incidence of infections caused by drug-resistant bacteria has created an urgent need for new antibacterial agents. We have discovered and optimized a novel class of antibiotics targeting PolC, the replicative DNA polymerase in Gram-positive bacteria. These agents exhibit broad spectrum activity against Gram-positive bacteria, including clinically important pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP), Streptococcus pyogenes (Group A strep), vancomycin-resistant enterococcus (VRE) and Clostridium difficile. In addition, compounds of this class are currently being evaluated for antibacterial activity in Gram-positive biothreat pathogens such as Bacillus anthracis. These agents demonstrate bactericidal activity, oral bioavailability, in vivo efficacy, a low propensity for toxicity and a low rate of spontaneous resistance. The mechanism of action has been unambiguously defined: the compounds inhibit an essential and novel molecular target involved in bacterial DNA synthesis and consequently circumvent existing mechanisms of antibiotic resistance. Although mechanistically similar to previously described PolC inhibitors of the anilino uracil class (Daly et al., 2000, Antimicrob. Agents Chemother. 44:2217), this compound series is chemically distinct, and displays more favorable microbiological potency and more desirable physical properties for drug development. We seek funding to advance this program from its current preclinical stage of lead optimization to the point of selecting a candidate compound for clinical development. The research plan leading to Investigational New Drug (IND) candidate selection comprises three stages. First, we will leverage information from our current structure- activity relationship (SAR) data coupled with a collection of 15 target-inhibitor co-crystals to perform structure- based lead optimization. Resulting compounds will be synthesized and will undergo extensive microbiological profiling. Compounds meeting the desired thresholds for potency and selectivity will progress to the second step, consisting of in vitro screens for metabolic stability and toxicity. This includes measuring degradation rates in human liver microsomes in order to estimate oral bioavailability and overall plasma exposure levels. Receptor binding assays that are predictive of known toxicity pathways have proven utility and help to ensure that the promising safety profile of these compounds is maintained throughout the lead optimization process. Compounds that pass the in vitro screens will progress to the final stage, consisting of in vivo testing of pharmacokinetics, efficacy and preliminary multi-dose toxicity. Collectively, these data should provide a detailed characterization of several lead compounds, supporting selection of the final IND candidate. A successful outcome would provide a long-term public health benefit in combating the rising tide of antibiotic- resistant infections that pose an acute threat to the general population, even those without predisposing risk factors. The alarming increase in incidence of infections caused by drug-resistant bacteria has created an urgent need for new antibacterial agents. The agents we have discovered and wish to develop represent a novel antibiotic class with broad spectrum Gram-positive antibacterial activity. The novel mechanism of action means that extant bacterial populations lack natural resistance. In the last forty years, very few new antibiotic classes have been brought to market, highlighting the pressing need for novel agents to combat resistance.

描述（由申请人提供）：耐药细菌引起的感染发生率的惊人增加迫切需要新的抗菌剂。我们发现并优化了一类针对 PolC（革兰氏阳性菌中的复制 DNA 聚合酶）的新型抗生素。这些药物对革兰氏阳性菌表现出广谱活性，包括临床上重要的病原体，如耐甲氧西林金黄色葡萄球菌 (MRSA)、耐青霉素肺炎链球菌 (PRSP)、化脓性链球菌（A 组链球菌）、耐万古霉素肠球菌 (VRE) ）和艰难梭菌。此外，目前正在评估此类化合物对革兰氏阳性生物威胁病原体（例如炭疽杆菌）的抗菌活性。这些药物表现出杀菌活性、口服生物利用度、体内功效、低毒性倾向和低自发耐药率。作用机制已明确定义：这些化合物抑制细菌 DNA 合成中重要的新型分子靶点，从而规避现有的抗生素耐药机制。尽管在机制上与之前描述的苯胺基尿嘧啶类 PolC 抑制剂相似（Daly 等人，2000，Antimicrob. Agents Chemother. 44:2217），但该化合物系列在化学上不同，并且表现出更有利的微生物效力和更理想的物理性质。药物开发。我们寻求资金来将该项目从目前先导化合物优化的临床前阶段推进到选择候选化合物进行临床开发的阶段。导致研究性新药 (IND) 候选药物选择的研究计划包括三个阶段。首先，我们将利用当前结构-活性关系 (SAR) 数据中的信息以及 15 种靶标-抑制剂共晶的集合来执行基于结构的先导化合物优化。所得化合物将被合成并进行广泛的微生物分析。满足效力和选择性所需阈值的化合物将进入第二步，包括代谢稳定性和毒性的体外筛选。这包括测量人肝微粒体的降解率，以估计口服生物利用度和总体血浆暴露水平。预测已知毒性途径的受体结合测定已被证明是有用的，并有助于确保在整个先导化合物优化过程中保持这些化合物的有希望的安全性。通过体外筛选的化合物将进入最后阶段，包括药代动力学、功效和初步多剂量毒性的体内测试。总的来说，这些数据应提供几种先导化合物的详细表征，支持最终 IND 候选药物的选择。成功的结果将在抗击不断上升的抗生素耐药性感染浪潮方面提供长期的公共卫生益处，这些感染对普通人群（甚至是那些没有诱发危险因素的人群）构成严重威胁。耐药细菌引起的感染发生率惊人增加，迫切需要新的抗菌药物。我们发现并希望开发的药物代表了一种具有广谱革兰氏阳性抗菌活性的新型抗生素。新颖的作用机制意味着现有的细菌群体缺乏天然抵抗力。在过去的四十年中，很少有新的抗生素类别被推向市场，这凸显了对抗耐药性的新药物的迫切需要。