Development of Novel Resistance-Modifying Agents for MRSA

 描述（由申请人提供）：抗生素是最重要和最广泛使用的药物之一。然而，它们的广泛和不受限制的使用增加了病原微生物发展耐药表型的速度。传统的方法集中在抗菌药物的开发上，这不能提供足够的化合物来解释耐药性的出现。现在迫切需要替代战略。我们最近开发了一种创新和系统的策略来开发耐药修饰剂（RMA），使耐药细菌对旧的抗菌药物重新敏感。RMA很有趣，因为它们可以延长目前具有成本效益的抗生素的使用寿命，并具有充分研究的毒性特征。此外，它们不针对必需基因，因此对细菌没有或几乎没有选择压力。对这种策略产生耐药性的机会比传统抗菌药物小。然而，已被证明临床上有用的唯一一类RMA是β-内酰胺酶抑制剂。利用生物启发的方法，我们最近发现 在耐甲氧西林金黄色葡萄球菌（MRSA）中，两种新的β-内酰胺增效剂支架不是β-内酰胺酶抑制剂。本申请的目的是进一步 优化这两种先导RMA，并证明其在体内小鼠模型中的功效。其基本原理是，这里开发的RMA可以作为具有新作用机制的候选药物，这将为研究性新药（IND）使能研究和随后的临床开发做好准备。具体而言，我们计划：在R21阶段，目标1。优化我们最近发现的RMAs的效力、选择性、哺乳动物毒性和药物样性质;目标2.优化我们的先导RMAs的药代动力学性质;在R33阶段，目标3。表征先导RMA在体内小鼠模型中的有效性，提高体内功效并减少潜在的责任;目的4.确定主要RMA的分子靶点。由于耐药细菌通常具有保守的耐药机制，因此也可以研究从这项工作中开发的体内活性RMA用于对抗其他耐药细菌的感染。这里确定的分子靶点也将激发使用靶向方法发现其他RMA。此外，拟议研究的成功完成也将验证我们的方法，并激发新型RMA的开发，以延长目前临床使用的其他抗菌药物的使用寿命。

 DESCRIPTION (provided by applicant): Antibiotics are among the most important and widely used medicines. Their extensive and unrestricted use has, however, increased the rate at which pathogenic microbes develop resistant phenotypes. Traditional approaches have focused on the development of antibacterials, which cannot provide enough compounds in the pipeline to account for resistance emergence. There is now a dire need for alternative strategies. We have recently developed an innovative and systematic strategy to develop resistance-modifying agents (RMAs) that re-sensitize resistant bacteria to old antibacterials. RMAs are intriguing because they can extend the useful life span of the current, cost-effective antibiotics with well-studied toxicity profiles. In addition, they do not target essential genes, and thus pose no or litle selective pressure on bacteria. The chance of developing resistance to this strategy is smaller than for conventional antibacterials. However, the only class of RMAs that have been proven clinically useful is β-lactamase inhibitors. Using a bio-inspired approach, we recently discovered two new scaffolds of β-lactam-potentiating reagents in methicillin-resistant Staphylococcus aureus (MRSA) that are not β-lactamase inhibitors. The objective of this application is to further optimize these two lead RMAs and demonstrate their efficacy in in vivo mouse models. The rationale is that the RMAs developed here may serve as drug candidates with novel mechanisms of action, which will be ready for investigational new drug (IND) enabling studies and subsequent clinical development. Specifically, we plan to: in R21 phase, Aim 1. optimize the potency, selectivity, mammalian toxicity, and drug-like properties of our recently discovered RMAs; Aim 2. optimize the pharmacokinetic properties of our lead RMAs; and in R33 phase, Aim 3. characterize the effectiveness of lead RMAs in in vivo mouse models, improve in vivo efficacy and reduce potential liabilities; Aim 4. identify the molecular targets of lead RMAs. As resistant bacteria often share conserved resistance mechanisms, the in vivo active RMAs developed form this work may also be investigated for use against infections from other resistant bacteria. The molecular targets identified here will also inspire the discovery of additional RMAs using targeted approaches. In addition, successful accomplishment of the proposed studies will also validate our approach and inspire the development of novel RMAs to extend the lifespan of other antibacterials currently used in the clinic.