Development of a Novel Class of Antibiotics with Activity Against Gram-Negative and Gram-Positive Pathogens

项目摘要 近年来，多药耐药(MDR)细菌感染的威胁导致在 鉴定新型抗菌药。这些努力已经导致几个新的药物类别被批准用于 革兰氏阳性感染；然而，由于在 革兰氏阴性菌是一种新型的广谱抗生素，自1968年以来一直没有推出过。此外， 革兰氏阴性药物开发流程中的大多数化合物都是现有抗生素的衍生物， 这增加了与批准的治疗方法交叉耐药的可能性。因此，存在着一种迫切需要 识别新型广谱抗生素，特别是那些对多药耐药病原体具有活性的抗生素。 一类抗菌药物是尼波霉素，由于其令人印象深刻的活性而特别有前景。 在细胞培养和动物模型中抗野生型和耐多药金黄色葡萄球菌和肠球菌 感染。然而，它们作为广谱制剂的使用受到限制，因为它们无法渗透到葛兰素史克- 阴性菌。因此，本申请的目的是扩大奈博霉素的活性谱 通过设计对革兰氏阴性和革兰氏阳性都具有适当活性的衍生品 病原体。这项工作将建立在最近确定了第一个奈博霉素类似物的初步研究的基础上 具有抗革兰氏阴性细菌的活性。在具体目标1中，将收集一系列奈博霉素衍生物 准备和评估抑制其生物靶标并在革兰氏阴性菌中蓄积的能力 细菌。这些研究的结果将被用来确定这些因素中的每一个是如何对 具有抗菌活性，并指导合成更具活性的衍生物。这些药物的治疗潜力 化合物将通过评估其耐受性、药代动力学参数 以及在小鼠体内的疗效。这些研究的完成将对人类健康产生重大影响 提供一系列具有显著活性的奈博霉素类似物，以对抗严重的耐多药革兰氏阳性和 革兰氏阴性病原菌及其作为新药开发的初步体内数据 班级。

Project Summary The threat of multidrug resistant (MDR) bacterial infections has in recent years led to increased efforts in identifying novel antibacterials. These efforts have resulted in the approval of several new drug classes for Gram-positive infections; however due to the additional challenges imposed by the outer membrane found in Gram-negative bacteria, a novel broad-spectrum agent has not been introduced since 1968. Furthermore, the majority of compounds in the Gram-negative drug development pipeline are derivatives of existing antibiotics, which increases the likelihood of cross-resistance with approved treatments. Thus, there exists a critical need to identify novel classes of broad-spectrum antibiotics, particularly those with activity against MDR pathogens. One class of antibacterials is the nybomycins, which are particularly promising due to their impressive activity against wild-type and MDR S. aureus and Enterococci species in both cell culture and animal models of infection. However their use as broad-spectrum agents is limited by their inability to penetrate into Gram- negative bacteria. It is, therefore, the objective of this application to expand the nybomycin spectrum of activity by designing derivatives that possess suitable activity against both Gram-negative and Gram-positive pathogens. This work will build upon preliminary studies that recently identified the first nybomycin analogue with activity against Gram-negative bacteria. In Specific Aim 1, a collection of nybomycin derivatives will be prepared and evaluated for the ability to inhibit their biological target and accumulate in Gram-negative bacteria. The results from these studies will be used to determine how each of these factors contribute to antibacterial activity and guide the synthesis of more active derivatives. The therapeutic potential of these compounds will be determined in Specific Aim 2 by evaluating their tolerability, pharmacokinetic parameters, and in vivo efficacy in mice. The completion of these studies will have a significant impact on human health by providing a series of nybomycin analogues with significant activity against serious MDR Gram-positive and Gram-negative pathogens as well as the preliminary in vivo data to support their development as a novel drug class.