A Bacitracin derivative for systemic use

全身使用的杆菌肽衍生物

• 批准号: 7324025
• 负责人: Ake P Elhammer
• 金额: $ 38.11万
• 依托单位: AUREOGEN BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7324025
• 关键词: 2-acetamidoethanethiol; Achievement; Adverse effects; Amino Acids; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Bacitracin; Bacteria; Bacterial Infections; Binding; Biological; Biological Factors; C-terminal; Chromatography; Clinical; Communities; Compatible; Complex; Condition; Coupled; Cyclic Peptides; Cyclization; Development; Dipeptides; Drug Compounding; Drug resistance; Enterococcus; Enzymes; Equipment and supply inventories; Evaluation; Future; Genes; Genus staphylococcus; Goals; High Pressure Liquid Chromatography; Hospitals; Human; In Vitro; Individual; Infection; Left; Long-Term Care; Marketing; Modification; Monitor; Multi-Drug Resistance; N-terminal; Nephrotoxic; Nickel; Nosocomial Infections; Numbers; Organism; Patients; Peptide Synthesis; Peptides; Pharmaceutical Preparations; Phase; Physiological; Property; Pseudomonas; Reaction; Recombinants; Resistance; Resort; S Phase; Sales; Screening procedure; Solid; Source; Staphylococcus aureus; Streptococcus; Structure; Synthesis Chemistry; Teicoplanin; Topical application; Vancomycin; Vancomycin resistant enterococcus; Work; bacitracin A; bacitracin F; bacitracin synthetase; chemical property; clinically relevant; cost; design; expression cloning; fungus; methicillin resistant Staphylococcus aureus; microorganism; nephrotoxicity; novel; pathogen; peptide synthase; urinary gonadotropin fragment; ward

DESCRIPTION (provided by applicant): The number of patients treated for antibiotics-resistant 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 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 powerful 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 strains of bacteria. It is important to realize, that 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 are projected to reach $30 billion in 2006. Several currently used antibacterial drugs belong to a group of natural products compounds known as cyclic peptides. Cyclic peptides are isolated from microorganisms such as bacteria or fungi. They are typically very specific, potent and efficacious drugs, but their use can be associated with significant side effects, and for some compounds the side effects are severe enough to impede clinical use. Moreover, although it may be known that the side effects can be reduced or even abolished by alterations to the structure of a cyclic peptide, this is rarely done. The reason for this is that the complexity and chemical properties of most cyclic peptides makes them unsuitable for cost-effective modifications, using currently available synthetic chemistry approaches. Compounds altered by this approach simply become too expensive. The overall goal of the project outlined in this proposal is to use a novel Chemo-Enzymatic Synthesis (CES) approach to identify the structural modifications required to eliminate, or at least significantly reduce, the nephrotoxicity associated with a cyclic peptide antibiotic that currently cannot be used systemically. The CES approach combines automated solid-phase peptide synthesis of linear precursor peptides, with enzymatic cyclization using a recombinant thioesterase (TE) domain derived from the relevant Non Ribosomal Peptide Synthetase (NRPS) complex. The approach effectively circumvents the most daunting problem associated with preparing cyclic peptides by synthetic chemistry: efficient, regiospecific cyclization of the linear precursor. Using CES, the assembly of modified cyclic peptides is simplified considerably and can be done at a cost compatible with commercial development. Successful achievement of the project goals will allow a considerably broader, systemic use of a very potent, broad-spectrum antibiotic and also generate a valuable addition to the current small inventory of drugs capable of treating multi drug-resistant infections. Due to a drastic increase in multi-drug resistant infections, in the last two decades, there is 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 essentially all clinically relevant Gram-positive organisms, including the multi drug- resistant pathogens.

描述（由申请人提供）：近年来，治疗耐药感染的患者数量急剧增加。最初的问题主要与医院获得性肠球菌感染有关，不仅已经进入一般社区，而且还发展到包括一些广泛和严重的病原体。耐药链球菌、葡萄球菌和假单胞菌菌株相当常见。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S。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强效药物，多年来一直是治疗耐药性感染的“最后手段”，但对某些细菌菌株也不再有效。重要的是要认识到，这些化合物的功效丧失使得患有多药耐药感染的患者的治疗选择非常少。显然，对具有新作用模式的新抗生素存在迫切的未满足的需求。此外，抗菌药物的总体市场很大，而且还在不断增长-预计2006年全球销售额将达到300亿美元。目前使用的几种抗菌药物属于一组天然产物化合物，称为环肽。环肽是从微生物如细菌或真菌中分离的。它们通常是非常特异、强效和有效的药物，但它们的使用可能与显著的副作用有关，并且对于某些化合物，副作用严重到足以阻碍临床使用。此外，尽管可能已知通过改变环肽的结构可以减少或甚至消除副作用，但很少这样做。其原因是大多数环肽的复杂性和化学性质使得它们不适合使用目前可用的合成化学方法进行成本有效的修饰。通过这种方法改变的化合物变得过于昂贵。本提案中概述的项目的总体目标是使用一种新的化学-酶促合成（CES）方法来确定消除或至少显着降低与目前不能全身使用的环肽抗生素相关的肾毒性所需的结构修饰。CES方法将线性前体肽的自动化固相肽合成与使用衍生自相关非核糖体肽合成酶（NRPS）复合物的重组硫酯酶（TE）结构域的酶促环化相结合。该方法有效地规避了与通过合成化学制备环肽相关的最令人生畏的问题：线性前体的高效、区域特异性环化。使用CES，修饰的环肽的组装被大大简化，并且可以以与商业开发相容的成本完成。项目目标的成功实现将使一种非常有效的广谱抗生素得到相当广泛的系统性使用，并为目前能够治疗多重耐药感染的少量药物库存提供宝贵的补充。 由于多重耐药感染的急剧增加，在过去的二十年中，对具有新作用模式的新抗菌药物的需求立即未得到满足。拟议项目将在目前相当有限的化合物库存中添加一种强效、有效、耐受性良好且经济的抗菌药物，该化合物对基本上所有临床相关的革兰氏阳性微生物（包括多重耐药病原体）均有效。