Discovery of a Novel Class of Boron-Based Antibacterials with Activity against Gram-Negative Bacteria
Discovery of a Novel Class of Boron-Based Antibacterials with Activity against Gram-Negative Bacteria
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DOI：
10.1128/aac.02058-12
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发表时间：
2013-03-01
影响因子：
4.9
通讯作者：
Plattner, Jacob J.
中科院分区：
文献类型：
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作者：
Hernandez, Vincent;Crepin, Thibaut;Plattner, Jacob J.
革兰氏阴性菌引起重症监护病房中约70%的感染。越来越多的导致这些感染的细菌分离株对目前可用的抗生素和许多正在开发的抗生素具有耐药性。大多数正在开发的药物是对现有药物类别的修改，仅部分克服现有的耐药机制。因此，需要具有真正新颖作用模式的新型革兰氏阴性抗菌药物来规避这些现有的耐药机制。我们以前已经确定了一种新的方法来抑制氨酰-tRNA合成酶，亮氨酰-tRNA合成酶（LeuRS），在真菌中通过氧杂硼杂环戊烯tRNA捕获（OBORT）机制。在此，我们展示了我们如何使用结构指导的方法修改OBORT机制，以开发一种新的基于硼的抗生素类，氨甲基苯并氧杂硼杂环戊烯，其抑制细菌亮氨酰-tRNA合成酶，并通过在很大程度上避开大肠杆菌和铜绿假单胞菌中的主要外排机制而对革兰氏阴性菌具有活性。铅类似物AN 3365对革兰氏阴性菌具有活性，包括携带NDM-1和KPC碳青霉烯酶的肠杆菌科以及铜绿假单胞菌。这种新型硼基抗菌剂AN 3365具有良好的小鼠药代动力学，对大肠杆菌有效。大肠杆菌和铜绿假单胞菌在小鼠大腿感染模型中的表达，这表明这类新型抗菌药物有可能解决这一未满足的医疗需求。
Gram-negative bacteria cause approximately 70% of the infections in intensive care units. A growing number of bacterial isolates responsible for these infections are resistant to currently available antibiotics and to many in development. Most agents under development are modifications of existing drug classes, which only partially overcome existing resistance mechanisms. Therefore, new classes of Gram-negative antibacterials with truly novel modes of action are needed to circumvent these existing resistance mechanisms. We have previously identified a new a way to inhibit an aminoacyl-tRNA synthetase, leucyl-tRNA synthetase (LeuRS), in fungi via the oxaborole tRNA trapping (OBORT) mechanism. Herein, we show how we have modified the OBORT mechanism using a structure-guided approach to develop a new boron-based antibiotic class, the aminomethylbenzoxaboroles, which inhibit bacterial leucyl-tRNA synthetase and have activity against Gram-negative bacteria by largely evading the main efflux mechanisms in Escherichia coli and Pseudomonas aeruginosa. The lead analogue, AN3365, is active against Gram-negative bacteria, including Enterobacteriaceae bearing NDM-1 and KPC carbapenemases, as well as P. aeruginosa. This novel boron-based antibacterial, AN3365, has good mouse pharmacokinetics and was efficacious against E. coli and P. aeruginosa in murine thigh infection models, which suggest that this novel class of antibacterials has the potential to address this unmet medical need.