Development of New Antibiotics Against Multidrug-Resistant Staphylococcus aureus

抗多重耐药金黄色葡萄球菌新型抗生素的研制

• 批准号: 9301456
• 负责人: Daniel S Pilch
• 金额: $ 39.12万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9301456
• 关键词: Address; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Area; Bacteria; Bacterial Drug Resistance; Bacterial Infections; Benchmarking; Biological Assay; Cardiotoxicity; Cell division; Cells; Centers for Disease Control and Prevention (U.S.); Clinical; Combined Modality Therapy; Cytochrome P450; Development; Dose; Drug Kinetics; Drug Targeting; Drug resistance; Ensure; Ethers; Evaluation; Filament; Formulation; Generations; Genes; Goals; Histopathology; Human; In Vitro; Infection; Innovative Therapy; Investigation; Investigational Drugs; Kinetics; Lead; Mammalian Cell; Mediating; Metabolism; Methicillin Resistance; Multi-Drug Resistance; Oral; Pathway interactions; Penicillin-Binding Proteins; Pharmaceutical Preparations; Pharmacology; Play; Potassium Channel; Prodrugs; Proteins; Public Health; Reporting; Research; Resistance; Role; Safety; Science; Staphylococcal Infections; Staphylococcus aureus; Technology; Temperature; Toxic effect; Toxicology; United States; Validation; Vancomycin-resistant S. aureus; Work; acute toxicity; bactericide; clinical practice; commensal microbes; design; drug candidate; effective therapy; genotoxicity; gut microbiota; improved; in vitro Assay; in vivo; innovation; liver metabolism; methicillin resistant Staphylococcus aureus; next generation; novel; novel therapeutics; pathogen; plasma protein Z; pre-clinical; resistance frequency; standard of care

Project Summary Antibacterial resistance is an increasingly serious threat to global public health. In recognition of this threat, the President’s Council of Advisors on Science and Technology (PCAST) has recently submitted a report to President Obama underscoring the urgency of ensuring “an effective arsenal of antibiotics that is continuously renewed.” Two pathogens recently identified by the CDC as major antibiotic resistance threats in the United States are methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus (VRSA). This proposal is premised on the hypothesis that developing new antibiotics with novel mechanisms of action will provide an innovative and effective therapy against MRSA and VRSA infections. The proposed project will develop drugs that act against a new antibacterial target (FtsZ, a protein essential for bacterial cell division) unexploited by any antibiotics in current clinical use. The proposal incorporates innovative solutions to problems of drug administration, elimination, and resistance that have hindered early efforts to develop drugs targeting bacterial cell division. Significantly, strong preliminary results are presented that provide validation for the innovative approach. The three areas to be investigated in this project are: 1. Identification of compounds that improve antibiotic efficacy. A problem associated with FtsZ-targeting compounds that have been generated to date is rapid elimination due to metabolism. This aim is geared toward the synthesis and evaluation of new compounds designed for resistance to metabolism and thus longer durations of action and enhanced efficacy in vivo. The studies in this aim will include assays to establish that our compounds are sparing of human gut microflora, as well as human and other mammalian cells. 2. Can other antibiotics function synergistically with our compounds? Synergistic combination therapy is an effective strategy for enhancing in vivo efficacy, while also minimizing the potential for toxicity and emergence of drug resistance. We hypothesize that our FtsZ-targeting compounds should act synergistically with drugs that target the penicillin binding proteins (PBPs), since both the PBPs and FtsZ play important roles in a common pathway leading to bacterial cell division. This aim is geared toward identifying PBP-targeting antibiotics that act synergistically in combination with our FtsZ-targeting compounds, while also reducing the frequency of resistance. 3. Selection of promising preclinical drug candidates. A critical step toward the selection of a preclinical candidate is a pharmacological safety assessment for potential toxicities. This aim is geared toward toxicological evaluation of our lead compounds with regard to genotoxicity (Ames mutagenicity), cardiotoxicity (hERG potassium channel inhibition), and single-dose acute toxicity. Together, these investigations will culminate in the selection of preclinical drug candidates primed for benchmarking Investigational New Drug (IND) studies. Ultimately, this will improve clinical practice by providing a new therapy for the treatment of multidrug-resistant (MDR) staphylococcal infections that will be effective even when current standard-of-care drugs fail.

项目摘要 抗生素耐药性是对全球公共卫生日益严重的威胁。认识到这一威胁， 总统科学技术顾问理事会最近提交了一份报告， 奥巴马总统强调了确保“一个有效的抗生素武库， 更新”。疾病预防控制中心最近确定的两种病原体是美国主要的抗生素耐药性威胁， 耐甲氧西林金黄色葡萄球菌（MRSA）和耐万古霉素S。金黄色葡萄球菌（VRSA）。 这一建议是基于这样的假设，即开发具有新作用机制的新抗生素， 将为MRSA和VRSA感染提供创新和有效的治疗。拟议项目将 开发针对新的抗菌靶点（FtsZ，细菌细胞分裂所必需的蛋白质）的药物 目前临床使用的任何抗生素都没有利用。该提案采用了创新的解决方案， 药物管理、消除和耐药性问题，这些问题阻碍了早期药物开发的努力 靶向细菌细胞分裂。值得注意的是，强有力的初步结果，提供验证 for the innovative创新approach方法.该项目将调查的三个领域是： 1.鉴定提高抗生素功效的化合物。与FtsZ靶向相关的问题 迄今为止产生的化合物是由于代谢而快速消除的。这一目标是面向 致力于合成和评估新的化合物，设计用于抵抗代谢，从而 更长的作用持续时间和增强的体内功效。这方面的研究将包括测定， 确定了我们化合物对人类肠道微生物区系以及人类和其它哺乳动物都有保护作用 细胞 2.其他抗生素能与我们的化合物协同作用吗？协同联合治疗 是增强体内功效的有效策略，同时还使毒性的可能性最小化， 耐药性的出现。我们假设我们的FtsZ靶向化合物应该起作用， 与靶向青霉素结合蛋白（PBP）的药物协同作用，因为PBP和FtsZ 在导致细菌细胞分裂的共同途径中发挥重要作用。这一目标是为了 确定与我们的FtsZ靶向组合协同作用的靶向PBP的抗生素 化合物，同时也降低了耐药的频率。 3.选择有前途的临床前候选药物。选择临床前药物的关键一步 候选药物是潜在毒性的药理学安全性评估。这一目标是为了 我们的先导化合物的遗传毒性（艾姆斯致突变性）毒理学评价， 心脏毒性（hERG钾通道抑制）和单剂量急性毒性。 总之，这些研究将最终选择临床前候选药物， 新药临床试验（IND）研究。最终，这将改善临床实践， 为治疗多重耐药（MDR）葡萄球菌感染提供了一种新的疗法， 即使在目前的标准治疗药物失效的情况下也有效。