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病率令人震惊地增加了对新抗菌剂的迫切需求。我们已经发现并优化了一种新型的抗生素POLC，即革兰氏阳性细菌中的复制性DNA聚合酶。 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艰难的。此外，目前正在评估该类别的化合物在革兰氏阳性生物治疗病原体（例如炭疽芽孢杆菌）中的抗菌活性。这些药物表现出杀菌活性，口服生物利用度，体内功效，毒性低倾向和自发性较低。作用机制已得到明确定义：这些化合物抑制了与细菌DNA合成有关的必不可少的新分子靶标，因此巩固了抗生素抗性的现有机制。尽管机械学上类似于先前描述的Anilino Uracil类的POLC抑制剂（Daly等，2000，Antimicrob。Antimicrob。AntertentsChemother。44：2217），但该化合物序列是化学上不同的，并且显示出更有利的微生物效力和更可取的物理特性。我们寻求资金将该计划从其当前的铅优化临床前阶段提高到为临床开发选择候选化合物的地步。导致研究新药（IND）候选选择的研究计划包括三个阶段。首先，我们将利用当前的结构活动关系（SAR）数据以及15个目标抑制剂共结晶的收集来实现基于结构的铅优化的信息。所得化合物将合成，并将进行广泛的微生物分析。满足所需效力和选择性阈值的化合物将发展到第二步，包括用于代谢稳定性和毒性的体外筛查。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。可预测已知毒性途径的受体结合测定已证明效用，并有助于确保在整个铅优化过程中保持这些化合物的有希望的安全性。通过体外筛查的化合物将发展到最后阶段，包括在体内测试药代动力学，功效和初步多剂量毒性。总的来说，这些数据应提供几种铅化合物的详细表征，并支持最终IND候选者的选择。成功的结果将为抗生素抗生素感染的潮流而造成急性威胁，即使是那些没有诱发风险因素的抗生素抗生素，这将为抗生素抗生素感染的潮流而产生长期的公共卫生益处。由耐药细菌引起的感染发病率的令人震惊的增加，迫切需要新的抗菌剂。我们发现并希望开发的代理代表具有广谱革兰氏阳性抗菌活性的新型抗生素类别。新型作用机理意味着现存的细菌种群缺乏自然抗性。在过去的四十年中，很少有新的抗生素类别被投放到市场上，这突出了对抗击抗性的新型抗生素的迫切需求。