Development of DksA-targeted Antibiotics for Treatment of Gram-negative Infections

开发用于治疗革兰氏阴性菌感染的 DksA 靶向抗生素

• 批准号: 10487785
• 负责人: Andres Vazquez-Torres
• 金额: --
• 依托单位: VA EASTERN COLORADO HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10487785
• 关键词: Abscess; Acute; Adsorption; Affect; Animal Model; Animals; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Appearance; Award; Azoles; Bacteria; Bacterial Antibiotic Resistance; Binding; Biochemistry; Bioinformatics; Biological; Biological Assay; Cell model; Cessation of life; Communicable Diseases; DNA-Directed RNA Polymerase; Dangerousness; Derivation procedure; Development; Disease; Drug Kinetics; Endowment; Evaluation; Excretory function; Exhibits; Family; Formulation; Funding; General Population; Genetic Transcription; Goals; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Grant; Health; Hospitals; Human; In Vitro; Infection; Investigation; Legal patent; Life; Metabolic; Metabolism; Military Personnel; Modeling; Modification; Molecular Target; Morbidity - disease rate; Mus; Necrosis; Oxidative Stress; Pathogenesis; Patients; Permeability; Pharmaceutical Preparations; Pharmacodynamics; Phylogenetic Analysis; Play; Progress Reports; Property; Proteins; Publishing; Rattus; Rod; Role; Salmonella; Salmonella enterica; Salmonella infections; Structure-Activity Relationship; Testing; Therapeutic; Toxic effect; Translations; Veterans; Virulence; Woman; World Health Organization; absorption; analog; antibiotic resistant infections; antimicrobial; clinically relevant; enteric pathogen; improved; inhibitor; men; military veteran; mortality; mouse model; new chemical entity; next generation; nitrosative stress; non-typhoidal Salmonella; novel; pathogen; pathogenic bacteria; pharmacokinetics and pharmacodynamics; prevent; programs; rational design; response; scaffold; therapeutic effectiveness; therapeutic evaluation; transcription factor

Antibiotic resistant infections disproportionately affect veterans and their families. Antibiotic resistant Gram-negative bacterial infections are associated with high rates of morbidity and mortality around the globe, including the men and women actively serving in the armed forces, veterans, and patients in VA hospitals. Options for antibiotic usage are in dangerous decline. Despite this health crisis, only 24 new antibiotics have been approved since 1987. Most newer antibiotics are modifications or reformulations of existing drugs. None of the recently approved antibiotics have novel mechanisms of action, severely limiting mechanistic diversity among available drugs. The transcription factor DksA, an essential component of the stringent response that regulates the pathogenesis of diverse Gram-negative bacteria, is highly conserved among Gram-negative pathogens but is absent from humans. Informed by bioinformatic modeling and structure-activity relationship (SAR), we have generated new chemical entities (NCE) that bind to DksA and have antimicrobial activity against nontyphoidal Salmonella and several other Gram-negative pathogens. Our preliminary pharmacokinetic evaluations indicate that one of our DksA inhibitors is absorbed and distributed in rats, and exhibits excellent antibiotic activity in an acute murine model of Salmonella infection. The ultimate goal of the proposed investigations is to develop soluble compounds against the DksA transcriptional regulator that are endowed with potent antimicrobial activity against Gram-negative pathogens. Specifically, we propose to 1) synthesize new DksA inhibitors with improved antimicrobial activity, and 2) characterize ADME (absorption, distribution, metabolism and excretion) properties and therapeutic potential of DksA inhibitors in animals. Synthesis of DksA inhibitors will contribute to the rational development of novel antibiotics against Gram-negative bacteria that affect veterans and the general population.

抗生素耐药性感染不成比例地影响退伍军人及其家人。抗生素抗性 革兰氏阴性细菌感染与周围环境的高发病率和死亡率相关。 地球仪，包括积极在武装部队服役的男女军人、退伍军人和退伍军人管理局的患者 医院的抗生素使用的选择正在危险地减少。尽管有这场健康危机， 自1987年以来，抗生素已被批准。大多数新的抗生素都是对 现有的药物。最近批准的抗生素都没有新的作用机制， 限制了可用药物之间的机制多样性。转录因子DksA是一种重要的 调节多种革兰氏阴性菌发病机制的严格反应组分， 在革兰氏阴性病原体中高度保守，但在人类中不存在。通知 生物信息学建模和构效关系（SAR），我们已经产生了新的化学实体 (NCE)其与DksA结合并具有抗非伤寒沙门氏菌和几种其它沙门氏菌抗微生物活性 革兰氏阴性病原体。我们初步的药代动力学评估表明我们的一种DksA 抑制剂在大鼠中被吸收和分布，并且在急性小鼠实验中表现出优异的抗生素活性。 沙门氏菌感染模型。拟议研究的最终目标是开发可溶性 具有强效抗微生物活性的针对DksA转录调节因子的化合物 对抗革兰氏阴性病原体具体而言，我们提出1）合成新的DksA抑制剂， 改善的抗微生物活性，和2）表征ADME（吸收、分布、代谢和 DksA抑制剂在动物中的治疗潜力。DksA抑制剂的合成 将有助于合理开发针对革兰氏阴性菌的新型抗生素， 退伍军人和普通民众。