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.

抗生素耐药性感染对退伍军人及其家人的影响尤为严重。抗生素耐药 革兰氏阴性细菌感染与周围地区的高发病率和死亡率相关。 全球，包括在武装部队中积极服役的男女军人、退伍军人和退伍军人管理局的患者 医院。抗生素使用的选择正在危险地减少。尽管存在这场健康危机，但只有 24 名新 抗生素自 1987 年起就已获得批准。大多数较新的抗生素都是以下抗生素的改良或重新配制： 现有药物。最近批准的抗生素都没有新的作用机制，严重 限制可用药物之间的机制多样性。转录因子 DksA，一种重要的转录因子 调节多种革兰氏阴性菌发病机制的严格反应的组成部分， 在革兰氏阴性病原体中高度保守，但在人类中不存在。通知者： 生物信息建模和构效关系（SAR），我们生成了新的化学实体 (NCE) 与 DksA 结合并对非伤寒沙门氏菌和其他几种具有抗菌活性 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 抑制剂在大鼠体内被吸收和分布，并在急性小鼠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的 针对 DksA 转录调节因子的化合物，具有有效的抗菌活性 针对革兰氏阴性病原体。具体来说，我们建议 1) 合成新的 DksA 抑制剂 改善抗菌活性，2) 表征 ADME（吸收、分布、代谢和 DksA 抑制剂在动物中的排泄）特性和治疗潜力。 DksA抑制剂的合成 将有助于合理开发针对影响革兰氏阴性菌的新型抗生素 退伍军人和普通民众。