Antibacterial Agents that Restrict the Emergence of Resistance

限制耐药性出现的抗菌药物

• 批准号: 8260867
• 负责人: Robert John Kerns
• 金额: $ 37.11万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-05 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8260867
• 关键词: Address; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antitubercular Agents; Binding; Biochemical; Biochemistry; Biological Assay; Cells; Chemicals; Clinical; Communicable Diseases; Complex; DNA Gyrase; DNA Topoisomerase IV; DNA Topoisomerases; Development; Disease; Drug Resistant Tuberculosis; Drug resistance; Escherichia coli; Evaluation; Exhibits; Extreme drug resistant tuberculosis; Fluoroquinolones; Funding; Generations; Goals; Growth; Infection; Lead; Life; Longevity; Microbiology; Modeling; Molecular Models; Multi-Drug Resistance; Mutation; Mycobacterium tuberculosis; Organism; Outcome; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Population Analysis; Prevalence; Process; Public Health; Publications; Quinolones; Recovery; Research; Resistance; Structure; Thinking; Tuberculosis; Work; bacterial resistance; base; cell type; chemical synthesis; design; expectation; fluoroquinolone resistance; inhibitor/antagonist; killings; molecular modeling; mutant; mycobacterial; novel; novel strategies; pathogen; progenitor; programs; public health relevance; quinolone resistance; success

DESCRIPTION (provided by applicant): The present application addresses the general problem of antibiotic resistance, in particular antibiotic-resistant tuberculosis (TB). The long-term goal of this research program is to develop new DNA gyrase inhibitors that are highly effective anti-tuberculosis (TB) agents with susceptible, multidrug-resistant, extensively drug- resistant, and completely drug-resistant forms of the disease. The specific goal of the present application is to develop a novel anti-mutant strategy for identifying lead antibacterial agents that will severely restrict the emergence of resistant mutants and to exploit the strategy to specifically identify anti-mutant gyrase inhibitors that are active against wild-type and quinolone-resistant mutants of M. tuberculosis. The anti-mutant strategy is based on the central hypothesis that new antibiotics having a closed or very narrow mutant selection window will severely restrict the rate at which resistant mutants emerge. Such antibiotics are expected to have increased clinical utility and longevity of use. Preliminary studies show that anti-mutant activity of new gyrase inhibitors does narrow the mutant selection window and restricts the recovery of induced mutants. Three specific aims have been developed to integrate medicinal chemistry, microbiology, biochemistry and molecular modeling studies into a new anti-mutant strategy and to identify lead structures for development as effective anti-TB agents. In Aims 1 and 2 we will develop new dione-class and C-7 aryl-quinolone-class agents that are active against wild-type cells, known quinolone-resistant gyrase mutants, and induced mutants generated against progenitor compounds within each class. In a third aim we will exploit two different models for agents binding to gyrase to identify and characterize new types of anti-mutant gyrase inhibitors. The expected outcome of this work is the generation of new lead gyrase inhibitors that exhibit a narrow mutant selection window and severely restrict the recovery of resistant mutants. Successful completion of these studies will provide a general framework for obtaining agents with excellent anti-mutant activity. The framework is expected to apply to many other structural and mechanistic antibiotic classes. PUBLIC HEALTH RELEVANCE: Antibiotic resistance has been recognized for more than a decade as a major threat to public health in the US and elsewhere; patients are now dying from once-treatable infections, and few new compounds are in the drug pipeline. Developing a new approach and new criteria for creating novel antibiotics that will restrict the emergence of resistant bacteria will lead to more effective, longer-lived compounds. Application of the ideas to tuberculosis will be significant because on a global basis tuberculosis kills more people than any other infectious disease and because drug-resistant tuberculosis is growing in prevalence.

描述（由申请人提供）：本申请解决了抗生素耐药性的普遍问题，特别是抗生素耐药性结核病（TB）。该研究计划的长期目标是开发新的 DNA 旋转酶抑制剂，它们是高效的抗结核 (TB) 药物，可治疗易感、多重耐药、广泛耐药和完全耐药的结核病。本申请的具体目标是开发一种新的抗突变策略，用于鉴定将严格限制抗性突变体出现的先导抗菌剂，并利用该策略来特异性鉴定对野生型有活性的抗突变促旋酶抑制剂。和结核分枝杆菌的喹诺酮抗性突变体。抗突变策略基于这样的中心假设：具有封闭或非常窄的突变选择窗口的新抗生素将严重限制耐药突变体出现的速度。预计此类抗生素将增加临床效用并延长使用寿命。初步研究表明，新型旋转酶抑制剂的抗突变活性确实缩小了突变体选择窗口并限制了诱导突变体的恢复。已经制定了三个具体目标，将药物化学、微生物学、生物化学和分子模型研究整合到新的抗突变策略中，并确定开发为有效抗结核药物的先导结构。在目标 1 和 2 中，我们将开发新的二酮类和 C-7 芳基喹诺酮类药物，这些药物对野生型细胞、已知的喹诺酮抗性旋转酶突变体以及针对每一类中的祖化合物产生的诱导突变体具有活性。第三个目标是，我们将利用两种不同的促旋酶结合剂模型来识别和表征新型抗突变促旋酶抑制剂。这项工作的预期结果是产生新的先导旋转酶抑制剂，其表现出狭窄的突变体选择窗口并严重限制抗性突变体的恢复。这些研究的成功完成将为获得具有优异抗突变活性的药物提供一个总体框架。该框架预计适用于许多其他结构和机制抗生素类别。 公共卫生相关性：十多年来，抗生素耐药性一直被认为是美国和其他地区公共卫生的主要威胁；现在，患者正死于曾经可治疗的感染，而且药物研发中几乎没有新化合物。开发一种新方法和新标准来制造新型抗生素，限制耐药细菌的出现，将产生更有效、寿命更长的化合物。将这些想法应用于结核病将具有重要意义，因为在全球范围内，结核病导致的死亡人数比任何其他传染病都多，而且耐药结核病的患病率正在不断上升。