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

抗生素耐药感染对退伍军人及其家人的影响不成比例。抗药性 革兰氏阴性细菌感染与周围地区的高发病率和死亡率有关 全球，包括在武装部队服役的男性和女性，退伍军人和退伍军人患者 医院。抗生素使用的选择正在危险地减少。尽管出现了这场健康危机，但只有24个新的 自1987年以来，抗生素一直被批准。大多数较新的抗生素是修改或重新配制的 现有的药物。最近批准的抗生素都没有新的作用机制，严重的 限制现有药物的机械多样性。转录因子DksA，一种必需的 这是调控各种革兰氏阴性细菌发病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。通知人 生物信息学建模和构效关系(SAR)，我们产生了新的化学实体 (NCE)与Dks A结合并对非伤寒沙门氏菌和其他几种细菌具有抗菌活性 革兰氏阴性病原体。我们的初步药代动力学评估表明，我们的其中一种Dks A 抑制剂在大鼠体内被吸收和分布，并在急性小鼠身上表现出良好的抗生素活性 沙门氏菌感染模型。拟议的调查的最终目标是开发出可解决的 具有很强的抗菌活性的化合物，具有抗Dks A转录调节作用 对抗革兰氏阴性病原体。具体地说，我们建议1)合成新的Dks A抑制剂 改进的抗菌活性，以及2)ADME(吸收、分布、代谢和 排泄)特性和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，这些细菌影响 退伍军人和普通民众。

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.