Generation of novel drugs against drug resistant bacteria through engineering of

通过工程设计产生抗耐药细菌的新药

• 批准号: 7535974
• 负责人: Ake P Elhammer
• 金额: $ 28.67万
• 依托单位: AUREOGEN BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-13 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7535974
• 关键词: Affinity Chromatography; Amino Acid Sequence; Amino Acids; Anabolism; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotic-resistant organism; Antibiotics; BMY-28117; Bacterial Antibiotic Resistance; Bacterial Infections; Biochemical; Biochemical Genetics; Biological; Class; Clinic; Clinical; Cloning; Cluster Analysis; Code; Communities; Compatible; Complex; Cyclic Peptides; DNA; Data; Depsipeptides; Development; Diphosphates; Disruption; Drug resistance; Drug usage; Elements; Engineering; Enterococcus; Epidermis; Equipment and supply inventories; Escherichia coli; Evaluation; Facility Construction Funding Category; Fatty Acids; Gene Cluster; Generations; Genes; Genetic; Genetic Engineering; Genomics; Genus staphylococcus; Goals; Hospitals; Human; In Vitro; Individual; Infection; Intellectual Property; Investments; Language; Left; Legal patent; Length; Libraries; Ligase; Lipids; Long-Term Care; Maps; Marketing; Mediating; Medical; Modification; Multi-Drug Resistance; Mus; Nosocomial Infections; Numbers; Organism; Patients; Peptides; Personal Satisfaction; Pharmaceutical Preparations; Phase; Phenotype; Polymerase Chain Reaction; Positioning Attribute; Preparation; Procedures; Production; Property; Proteins; Pseudomonas; Public Health; Publishing; Range; Reaction; Recombinants; Regulation; Resistance; Resort; Sales; Screening procedure; Shotgun Sequencing; Specificity; Staphylococcus aureus; Streptococcus; Streptococcus pneumoniae; Streptococcus pyogenes; Structure; Systemic infection; Teicoplanin; Testing; Therapeutic; Today; Vancomycin; Vancomycin resistant enterococcus; Variant; Walking; analog; animal data; antimicrobial; clinically relevant; commercialization; concept; design; drug market; drug resistant bacteria; empedopeptin; expression vector; gene cloning; gene function; his6 tag; hydroxy fatty acid; improved; in vivo; mutant; novel; pathogen; peptide synthase; size; ward

DESCRIPTION (provided by applicant): The number of patients treated for antibiotics-resistant bacterial infections has increased drastically in recent years. What started as a problem primarily associated with hospital-acquired Enterococcus infections, has not only moved into the general community, but also grown to include a number of widespread and serious pathogens. Drug-resistant Streptococci, Staphylococci, Enterococci and Pseudomonas strains are quite common. Currently as many as 70% of hospital-acquired infections in the US are resistant to at least one antibiotic, and about 40% of S. aureus infections are multidrug-resistant. Even drugs like Vancomycin and Teicoplanin, which for years represented the "agents of last resort" for treatment of antibiotics-resistant infections, are no longer efficacious against certain pathogen strains. The loss of efficacy of these compounds leaves very few treatment options for patients with multi-drug resistant infections. Clearly, there is an immediate unmet need for new antibiotics with novel modes of action. Moreover, the overall market for antibacterial drugs is large and growing - world-wide sales reached $30 billion in 2006. Early published data suggest that empedopeptin, a cyclic peptide produced by Empedobacter haloabium, has considerable potency towards a wide range of Gram positive organisms, in vitro. This data also suggest that the compound is well tolerated in mice and quite efficacious against systemic infections of Staphylococcus aureus, Streptococcus pyogenes and Streptococcus pneumoniae. Nonetheless, although discovered over 20 years ago, empedopeptin has not been developed into a commercial product. A recent, in vitro evaluation of empedopeptin has revealed that the compound also has significant potency against most contemporary, drug-resistant, Gram-positive organisms, including meticillin-resistant S. aureus (MRSA), meticillin-resistant S. epidermis (MRSE) and vancomycin-resistant Enterococci (VRE). Together with the published animal data, this suggests that empedopeptin may have the properties required for development into a drug for the treatment of infections caused by today's antibiotics-resistant organisms. However, a lack of patent protection together and somewhat high MIC values towards several pathogens currently constitutes a barrier to development of the compound. The overall goal of the project outlined in this proposal is to use of a genetic engineering approach to generate novel derivatives of the antibacterial compound empedopeptin. This will allow improvement of the compound's therapeutic properties, as well as creation of an intellectual property situation that is compatible with commercial development of the compound as a drug for the treatment of antibiotics-resistant bacterial infections. However, an absolute prerequisite for any genetic engineering-mediated structural modifications of empedopeptin is availability of the corresponding (currently unknown) biosynthesis gene. Consequently, the goal of Phase I is to identify, isolate and characterize this gene. PUBLIC HEALTH RELEVANCE: The drastic increase in multi-drug resistant infections, during last two decades, has generated an immediate unmet need for new antibacterial drugs with novel modes of action. The proposed project will add a potent, efficacious, well-tolerated and economical antibacterial drug to a currently quite limited inventory of compounds with efficacy towards a broad range of clinically relevant drug- and multi-drug resistant Gram-positive pathogens.

描述（由申请人提供）：近年来，接受抗生素耐药性细菌感染治疗的患者数量急剧增加。最初主要与医院获得性肠球菌感染有关的问题，现在不仅蔓延到普通社区，而且还发展到包括许多广泛传播的严重病原体。耐药链球菌、葡萄球菌、肠球菌和假单胞菌菌株相当常见。目前，美国多达 70% 的医院获得性感染对至少一种抗生素具有耐药性，约 40% 的金黄色葡萄球菌感染具有多重耐药性。即使是像万古霉素和替考拉宁这样多年来代表治疗抗生素耐药性感染的“最后手段”的药物，也不再对某些病原体菌株有效。这些化合物失效后，多重耐药感染患者的治疗选择就很少了。显然，对具有新颖作用方式的新型抗生素的需求迫切需要满足。此外，抗菌药物的整体市场规模巨大且不断增长 - 2006 年全球销售额达到 300 亿美元。早期公布的数据表明，Empedopeptin（一种由 Empedobacter haloabium 产生的环肽）对多种革兰氏阳性生物体具有相当大的效力，体外。该数据还表明，该化合物在小鼠中具有良好的耐受性，并且对金黄色葡萄球菌、化脓性链球菌和肺炎链球菌的全身感染非常有效。尽管如此，尽管恩培肽在 20 多年前就被发现，但尚未开发成商业产品。最近对 empedopeptin 的体外评估表明，该化合物对大多数当代耐药革兰氏阳性微生物也具有显着功效，包括耐甲氧西林金黄色葡萄球菌 (MRSA)、耐甲氧西林表皮葡萄球菌 (MRSE)和耐万古霉素肠球菌（VRE）。结合已发表的动物数据，这表明 Empedopeptin 可能具有开发成治疗当今抗生素耐药生物体引起的感染的药物所需的特性。然而，缺乏专利保护以及对多种病原体的 MIC 值较高，目前构成了该化合物开发的障碍。该提案中概述的项目的总体目标是利用基因工程方法生成抗菌化合物 empedopeptin 的新型衍生物。这将改善该化合物的治疗特性，并创造与该化合物作为治疗抗生素耐药性细菌感染的药物的商业开发相容的知识产权状况。然而，任何基因工程介导的 empedopeptin 结构修饰的绝对先决条件是相应（目前未知）生物合成基因的可用性。因此，第一阶段的目标是识别、分离和表征该基因。公共卫生相关性：过去二十年中，多重耐药性感染急剧增加，导致对具有新颖作用方式的新型抗菌药物的迫切需求尚未得到满足。拟议的项目将为目前相当有限的化合物库存添加一种强效、有效、耐受性良好且经济的抗菌药物，对广泛的临床相关耐药和多重耐药革兰氏阳性病原体有效。