Methicillin-resistant Staphylococcus aureus (MRSA) is the leading cause of recurrent infections in humans including endocarditis, pneumonia, and toxic shock syndrome. Novel therapeutics to treat MRSA and other resistant bacteria are urgently needed. Adjuvant therapy, which uses a non-toxic compound to repotentiate the toxic effects of an existing antibiotic, is an attractive response to the growing resistance crisis. Herein, we describe the evaluation of structurally related, FDA-approved tricyclic amine antidepressants that selectively repotentiate MRSA to β-lactam antibiotics. Our results identify important structural features of the tricyclic amine class for β-lactam adjuvant activity. Furthermore, we describe the mechanism of action for our lead compound, amoxapine, and illustrate that it represses the mRNA levels of key β-lactam resistance genes in response to β-lactam treatment. This work is novel in that it highlights an important class of small molecules with the ability to simultaneously inhibit production of both β-lactamase and penicillin binding protein 2a.

译文

耐甲氧西林金黄色葡萄球菌 (MRSA) 是人类反复感染的主要原因,包括心内膜炎,肺炎和中毒休克综合征。迫切需要治疗MRSA和其他耐药细菌的新型疗法。辅助疗法使用无毒化合物来增强现有抗生素的毒性作用,是对日益增长的耐药性危机的一种有吸引力的反应。在本文中,我们描述了结构相关的,FDA批准的三环胺抗抑郁药的评估,可选择性地将MRSA转化为 β-内酰胺类抗生素。我们的结果确定了三环胺类对 β-内酰胺佐剂活性的重要结构特征。此外,我们描述了我们的铅化合物阿莫沙平的作用机理,并说明了它在响应 β-内酰胺治疗时抑制关键的 β-内酰胺抗性基因的mRNA水平。这项工作是新颖的,因为它突出了一类重要的小分子,具有同时抑制 β-内酰胺酶和青霉素结合蛋白2a产生的能力。

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