Department of Chemistry, High Point University, High Point, North Carolina.
Chem Biol Drug Des. 2018 Nov;92(5):1822-1829. doi: 10.1111/cbdd.13361. Epub 2018 Jul 18.
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.
耐甲氧西林金黄色葡萄球菌（MRSA）是导致人类反复感染的主要原因，包括心内膜炎、肺炎和中毒性休克综合征。急需新型疗法来治疗 MRSA 和其他耐药菌。佐剂疗法使用无毒化合物来增强现有抗生素的毒性作用，是应对日益严重的耐药危机的一种有吸引力的反应。本文描述了对结构相关的、已获得 FDA 批准的三环胺抗抑郁药的评估，这些药物选择性地增强了 MRSA 对β-内酰胺类抗生素的敏感性。我们的结果确定了三环胺类药物增强β-内酰胺类抗生素活性的重要结构特征。此外，我们还描述了我们的先导化合物阿莫沙平的作用机制，并阐明它在β-内酰胺类药物治疗时抑制关键β-内酰胺类耐药基因的 mRNA 水平。这项工作的新颖之处在于它强调了一类具有同时抑制β-内酰胺酶和青霉素结合蛋白 2a 产生能力的重要小分子。
