Targeting superbugs: discovery and development of new broad-spectrum lipopeptides

针对超级细菌：新型广谱脂肽的发现和开发

• 批准号: 8662691
• 负责人: Jian Li
• 金额: $ 82.92万
• 依托单位: MONASH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8662691
• 关键词: Acinetobacter baumannii; Americas; Amino Acids; Animals; Anti-Bacterial Agents; Antibiotic Therapy; Antibiotics; Antimicrobial Resistance; Attention; Australia; Back; Bacterial Infections; Biochemical; Categories; Charge; Colistin; Communicable Diseases; Country; Data; Development; Disease Outbreaks; Dose; Drug Formulations; Drug Kinetics; Drug resistance; Enterobacter; Enterobacter cloacae; Enterococcus faecium; Evaluation; Exhibits; Feedback; Figs - dietary; Financial Support; Gram-Negative Bacteria; Gram-Positive Bacteria; Health; Hemolysis; Hospitals; Human; Hydrophobic Interactions; Infection; Intravenous; Klebsiella pneumonia bacterium; Lead; Learning; Life; Lipid A; Lipopolysaccharides; Lung; Measures; Medical; Microscopic; Modeling; Modification; Multi-Drug Resistance; Mus; Organism; Paper; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology; Phase; Physicians; Polymyxin B; Polymyxin Resistance; Polymyxins; Positioning Attribute; Property; Pseudomonas aeruginosa; Public Health; Publishing; Rattus; Reporting; Research; Research Design; Research Proposals; Resistance; Resistance development; Safety; Series; Societies; Staging; Staphylococcus aureus; Structure; Structure-Activity Relationship; Thigh structure; Time; Toxic effect; Toxicology; Universities; World Health; antimicrobial; bacterial resistance; bactericide; base; biodefense; cytotoxicity; design; experience; feeding; improved; in vivo; man; microorganism; model design; nephrotoxicity; novel; pathogen; phase 1 study; process optimization; resistant strain; scale up; transcriptomics

DESCRIPTION (provided by applicant): As highlighted in the 'Bad Bugs, No Drugs' campaign by the Infectious Diseases Society of America (IDSA), "There simply aren't enough new drugs in the pharmaceutical pipeline to keep pace with drug-resistant bacterial infections, so-called 'superbugs'." Numerous hospitals worldwide have experienced outbreaks of infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Enterobacter species, Enterococcus faecium and Staphyloccocus aureus. All of these pathogens are on the IDSA 'hit list' of the six top-priority dangerous microorganisms "ESKAPE" that require the most urgent attention to discover new antibiotics. Sadly, no novel antibiotics against MDR P. aeruginosa, A. baumannii and K. pneumoniae will be available for many years to come. Polymyxins (i.e. colistin and polymyxin B) are now being used as the 'last-line' of therapy for infections caused by these very problematic MDR pathogens. Very unfortunately, emergence of polymyxin resistance has been increasingly reported recently. In essence, resistance to polymyxins implies a total lack of antibiotics for treatment of life-threatening infections caused by these Gram-negative bacteria. Research Design: Using a new structure-activity relationship (SAR)-based mechanistic model for polymyxins, novel lipopeptides we designed and synthesized showed very promising activity against polymyxin-resistant MDR strains of P. aeruginosa, A. baumannii and K. pneumoniae, while maintaining activity against polymyxin- susceptible strains. Remarkably, a number of these lipopeptides were also active against MDR strains of two Gram-positive 'superbugs'. Our approach, based upon modeling the interaction between polymyxins and the lipid A of lipopolysaccharides (LPS), is novel. Our hypothesis is that polymyxin resistance in Gram-negative and/or Gram-positive bacteria is overcome by modifications of the core polymyxin structure. A systematic funneling approach with feedback loops will allow us to 'learn' as much as possible at early stages about the SAR to inform the design of superior lipopeptides. Aim 1: To design, synthesize and evaluate microbiologically ~125 novel lipopeptides active against: (a) polymyxin-resistant Gram-negative 'superbugs' using an SAR-based mechanistic model; and (b) problematic MDR Gram-positive E. faecium and S. aureus. Three series of lipopeptides will be designed and synthesized to enhance (i) hydrophobic interactions, (ii) polar interactions, and (iii) a combination of both, with lipid A. Pharmacological evaluations in Specifi Aims 3 and 4 will provide important information for improvement of the model and design of superior lipopeptides. Aim 2: To elucidate the mechanism(s) of activity of the lipopeptides against both Gram-negative and -positive pathogens. Confocal microscopic, transcriptomic and biochemical approaches will be employed to examine the antibacterial activity of our lipopeptides against both Gram-negative and -positive pathogens. The results will provide valuable mechanistic information for designing more active lead lipopeptides (Specific Aim 1). Aim 3: To conduct lead optimization based upon characterization of pharmacodynamics, potential for development of resistance and toxicity, and physicochemical and pharmacokinetic properties. In the lead optimization process, we will measure the minimum inhibitory and bactericidal concentrations of lipopeptides against a large panel of strains. Potential for development of resistance, hemolysis, cytotoxicity and nephrotoxicity, and physicochemical and pharmacokinetic properties, will be assessed. In addition, the interactions with LPS will be studied. Information obtained will be fed back to improve the SAR model (Specific Aim 1). Advanced lead lipopeptides will be identified and proceed to animal studies in Specific Aim 4. Aim 4: To evaluate the in vivo efficacy, toxicity and PK/PD properties for 5 - 10 superior lipopeptides using animal infection models, and to identify 1 - 2 candidates for IND/Phase-1 evaluations. Neutropenic mouse thigh and lung infection models will be employed to evaluate the in vivo efficacy of the advanced leads. Formulations for intravenous delivery will be developed for the candidates before the first dose in man. Aim 5: To conduct IND-enabling toxicology studies. Scale-up of the active pharmaceutical ingredient to conduct range-finding toxicology studies in rats and non-rodent species, and ultimately IND-enabling GLP toxicology and safety pharmacology studies. Even though it is beyond the scope of this RFA, we are very enthusiastic that the identified candidates will be taken to the IND/Phase 1 study with financial support from Mpex. Significance: As highlighted in the WHO World Health Day 2011, "no action today means no cure tomorrow". This project holds great promise for development of novel antibiotics against the six top-priority ESKAPE 'superbugs' identified by the IDSA, in particular polymyxin-resistant MDR P. aeruginosa, A. baumannii and K. pneumoniae. Overall, this project targets the urgent global unmet medical need and responds in a timely manner to the recent global call for discovery of new antibiotics: The 10 x '20 Initiative.

描述（由申请人提供）：正如美国传染病协会（IDSA）在“坏虫子，没有药物”运动中所强调的那样，“制药管道中根本没有足够的新药来跟上耐药细菌感染的步伐，所谓的'超级细菌'。“全球许多医院都经历了由多重耐药铜绿假单胞菌、鲍曼不动杆菌、肺炎克雷伯菌、肠杆菌属、屎肠球菌和金黄色葡萄球菌引起的感染爆发。所有这些病原体都在IDSA的六种最优先危险微生物“ESKAPE”的“打击名单”上，这些微生物需要最迫切的关注来发现新的抗生素。 不幸的是，没有新的抗生素对耐多药铜绿假单胞菌，A。鲍曼不动杆菌和K. pneumoniae肺炎will be available可用for many许多years年份to come.多粘菌素（即粘菌素和多粘菌素B）现在被用作治疗这些非常有问题的MDR病原体引起的感染的“最后一线”。非常不幸的是，最近越来越多地报道了多粘菌素耐药性的出现。从本质上讲，对多粘菌素的耐药性意味着完全缺乏抗生素来治疗这些革兰氏阴性菌引起的危及生命的感染。 研究设计：利用一种新的基于构效关系（SAR）的多粘菌素作用机理模型，我们设计并合成的新型脂肽对铜绿假单胞菌（P. aeruginosa，A.鲍曼不动杆菌和K.肺炎，同时保持对多粘菌素敏感菌株的活性。值得注意的是，这些脂肽中的一些也对两种革兰氏阳性“超级细菌”的MDR菌株有活性。我们的方法，基于多粘菌素和脂多糖（LPS）的脂质A之间的相互作用建模，是新颖的。我们的假设是，革兰氏阴性和/或革兰氏阳性细菌中的多粘菌素耐药性通过核心多粘菌素结构的修饰而克服。具有反馈回路的系统性功能方法将允许我们在早期阶段尽可能多地“学习"SAR，以告知上级脂肽的设计。 目标1：设计、合成和微生物学评价~125种新型脂肽，其活性针对：（a）使用基于SAR的机制模型的多粘菌素耐药革兰氏阴性“超级细菌”;和（B）有问题的MDR革兰氏阳性E. faecium和S.金黄色。将设计和合成三个系列的脂肽，以增强与脂质A的（i）疏水相互作用，（ii）极性相互作用和（iii）两者的组合。Specifi目的3和4中的药理学评价将为模型的改进和上级脂肽的设计提供重要信息。 目的2：阐明脂肽对革兰氏阴性菌和革兰氏阳性菌的作用机制。将采用共聚焦显微镜、转录组学和生物化学方法来检查我们的脂肽对革兰氏阴性和阳性病原体的抗菌活性。这些结果将为设计更有活性的先导脂肽（具体目标1）提供有价值的机理信息。 目标3：根据药效学特征、耐药性和毒性的可能性以及理化和药代动力学特性进行电极导线优化。在先导优化过程中，我们将测量脂肽对一大组菌株的最小抑制和杀菌浓度。将评估产生耐药性、溶血、细胞毒性和肾毒性的可能性，以及理化和药代动力学特性。此外，还将研究与LPS的相互作用。所获得的信息将被反馈，以改进SAR模型（具体目标1）。将在特定目标4中识别高级铅脂肽并继续进行动物研究。 目标4：使用动物感染模型评价5 - 10种上级脂肽的体内疗效、毒性和PK/PD特性，并确定1 - 2种候选药物用于IND/I期评价。将采用中性粒细胞减少小鼠大腿和肺部感染模型来评价高级电极导线的体内有效性。将在人体首次给药前为候选药物开发静脉给药制剂。 目标5：开展IND使能毒理学研究。扩大活性药物成分的规模，以在大鼠和非啮齿类动物种属中进行剂量范围探索毒理学研究，并最终进行IND使能GLP毒理学和安全药理学研究。 尽管这超出了RFA的范围，但我们非常希望在Mpex的财政支持下，将确定的候选人纳入IND/I期研究。意义：正如世卫组织2011年世界卫生日所强调的，“今天不采取行动，明天就无法治愈”。该项目为开发针对IDSA确定的六种最优先ESKAPE“超级细菌”的新型抗生素，特别是耐多粘菌素的MDR铜绿假单胞菌，A。鲍曼不动杆菌和K.肺炎。总的来说，该项目针对全球迫切的未满足的医疗需求，并及时响应最近全球发现新抗生素的呼吁：10 x '20倡议。