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: 8478028
• 负责人: Jian Li
• 金额: $ 75.5万
• 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/8478028
• 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）：正如美国传染病学会（IDSA）在“坏细菌，没有药物”运动中强调的那样，“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，即所谓的“超级细菌”。”世界各地的许多医院都经历过由多重耐药（MDR）铜绿假单胞菌、鲍曼不动杆菌、肺炎克雷伯菌、肠杆菌、屎肠球菌和金黄色葡萄球菌引起的感染暴发。所有这些病原体都在IDSA列出的六种最优先的危险微生物“ESKAPE”的“打击名单”上，需要最紧急的关注，以发现新的抗生素。遗憾的是，在未来的许多年里，还没有针对耐多药铜绿假单胞菌、鲍曼假单胞菌和肺炎克雷伯菌的新型抗生素。多粘菌素（即粘菌素和多粘菌素B）现在被用作治疗由这些非常有问题的耐多药病原体引起的感染的“最后一线”。非常不幸的是，最近关于多粘菌素耐药性的报道越来越多。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由这些革兰氏阴性菌引起的危及生命的感染。研究设计：利用基于构效关系（SAR）的多粘菌素作用机制模型，我们设计合成的新型脂肽对耐多粘菌素多耐药菌株铜绿假单胞菌（P. aeruginosa）、鲍曼假单胞菌（a . baumannii）和肺炎克雷伯菌（K. pneumoniae）表现出良好的活性，同时对多粘菌素敏感菌株保持活性。值得注意的是，许多这些脂肽对两种革兰氏阳性“超级细菌”的耐多药菌株也有活性。我们的方法，基于建模多粘菌素和脂多糖（LPS）的脂质A之间的相互作用，是新颖的。我们的假设是，革兰氏阴性和/或革兰氏阳性细菌的多粘菌素耐药性是通过修改核心多粘菌素结构来克服的。带有反馈回路的系统漏斗方法将使我们能够在SAR的早期阶段尽可能多地“学习”，从而为优质脂肽的设计提供信息。