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的发病率和死亡率高有关 地球仪，包括在武装部队，退伍军人和VA中积极服役的男人和女人 医院。使用抗生素的选择正在危险下降。尽管有这种健康危机，但只有24个新 自1987年以来已批准抗生素。大多数新的抗生素是对 现有药物。最近批准的抗生素都没有新颖的作用机理，严重 限制可用药物的机械多样性。转录因子DKSA，必不可少的 严格反应的组成部分，该反应调节了革兰氏阴性细菌的发病机理 在革兰氏阴性病原体中是高度保守的，但人类不存在。告知 生物信息学建模和结构活性关系（SAR），我们生成了新的化学实体 （NCE）与DKSA结合并具有抗菌活性与非肾脏沙门氏菌和其他几个 革兰氏阴性病原体。我们的初步药代动力学评估表明我们的DKSA之一 抑制剂被吸收并分布在大鼠中，并在急性鼠中表现出极好的抗生素活性 沙门氏菌感染的模型。拟议调查的最终目标是开发可溶性 针对具有有效抗菌活性的DKSA转录调节器的化合物 针对革兰氏阴性病原体。具体而言，我们建议1）与 改善抗菌活性，2）表征ADME（吸收，分布，代谢和 DKSA抑制剂在动物中的特性和治疗潜力。 DKSA抑制剂的合成 将有助于对影响革兰氏阴性细菌的新型抗生素的合理发展 退伍军人和一般人口。