Generation of novel drugs against drug resistant bacteria through engineering of

描述(申请人提供)：近年来，因抗药性细菌感染而接受治疗的患者数量急剧增加。最初的问题主要与医院获得的肠球菌感染有关，现在不仅进入了普通社区，而且还包括一些广泛和严重的病原体。耐药链球菌、葡萄球菌、肠球菌和假单胞菌较为常见。目前，在美国，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。即使像万古霉素和替考拉宁这样的药物，多年来一直是治疗抗生素耐药感染的“最后手段”，对某些病原体菌株也不再有效。这些化合物的疗效丧失后，对多重耐药感染患者的治疗选择很少。显然，对具有新作用模式的新抗生素的迫切需求尚未得到满足。此外，抗菌药物的总体市场规模很大，而且还在不断增长--2006年全球销售额达到300亿美元。早期发表的数据表明，恩培多肽，一种由嗜盐芽孢杆菌产生的环肽，在体外对广泛的革兰氏阳性菌具有相当大的效力。这一数据还表明，该化合物在小鼠中具有良好的耐受性，对金黄色葡萄球菌、化脓性链球菌和肺炎链球菌的系统性感染相当有效。然而，尽管在20多年前就发现了恩培多肽，但它还没有被开发成商业产品。最近对恩培多肽的体外评估显示，该化合物还对大多数当代、耐药、革兰氏阳性细菌具有显著的效力，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)和万古霉素耐药肠球菌(VRE)。结合已发表的动物数据，这表明恩培多肽可能具有开发为治疗由当今抗生素耐药微生物引起的感染的药物所需的特性。然而，缺乏专利保护，以及对几种病原体的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使用基因工程方法来产生抗菌化合物恩培多肽的新衍生物。这将改善该化合物的治疗性能，并创造一种与该化合物作为治疗抗药性细菌感染药物的商业开发相兼容的知识产权状况。然而，任何由基因工程介导的恩佩多肽结构修饰的绝对先决条件是获得相应的(目前尚不清楚的)生物合成基因。因此，第一阶段的目标是识别、分离和鉴定该基因。与公共卫生相关：在过去20年中，多重耐药感染急剧增加，导致对具有新作用模式的新抗菌药物的迫切需求尚未得到满足。拟议的项目将在目前相当有限的化合物库存中增加一种有效、有效、耐受性良好和经济的抗菌药物，对广泛的临床相关药物和多重耐药革兰氏阳性病原体有效。

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.