四环吲哚啉类化合物作为一类新型的耐甲氧西林金黄色葡萄球菌β-内酰胺类选择性耐药修饰剂。
Tetracyclic indolines as a novel class of β-lactam-selective resistance-modifying agent for MRSA.
作者信息
Zhu Yugen, Cleaver Lakota, Wang Wei, Podoll Jessica D, Walls Shane, Jolly Austin, Wang Xiang
机构信息
Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA.
Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309, USA.
出版信息
Eur J Med Chem. 2017 Jan 5;125:130-142. doi: 10.1016/j.ejmech.2016.09.034. Epub 2016 Sep 10.
Antibiotic-resistant bacterial infections have seen a marked increase in recent years, while antibiotic discovery has waned. Resistance-modifying agents (RMA) offer an intriguing alternative strategy to fight against resistant bacteria. Here we report the discovery, antibiotic profiling, and structure-activity relationships of a novel class of RMAs, tetracyclic indolines. These selectively potentiate β-lactam antibiotics in methicillin-resistant Staphylococcus aureus (MRSA) without antibacterial or β-lactamase inhibitory activity on their own. The most potent analogue, 6a, showed strong potentiation of amoxicillin/clavulanic acid in a variety of hospital-acquired and community-acquired MRSA strains with low mammalian toxicity. These compounds may be further developed to extend the clinic life span of β-lactam antibiotics.
近年来，抗生素耐药性细菌感染显著增加，而抗生素的发现却有所减少。耐药性修饰剂（RMA）为对抗耐药细菌提供了一种引人关注的替代策略。在此，我们报告了一类新型RMA——四环吲哚啉的发现、抗生素谱分析及构效关系。这些化合物能在耐甲氧西林金黄色葡萄球菌（MRSA）中选择性增强β-内酰胺类抗生素的活性，而自身并无抗菌活性或β-内酰胺酶抑制活性。最有效的类似物6a，在多种医院获得性和社区获得性MRSA菌株中对阿莫西林/克拉维酸表现出强烈的增强作用，且对哺乳动物毒性较低。这些化合物可能会进一步开发，以延长β-内酰胺类抗生素的临床使用寿命。
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