β-Lactamase inhibition by avibactam in Mycobacterium abscessus
β-Lactamase inhibition by avibactam in Mycobacterium abscessus
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DOI：
10.1093/jac/dku510
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发表时间：
2015-04-01
影响因子：
5.2
通讯作者：
Arthur, Michel
中科院分区：
文献类型：
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作者：
Dubee, Vincent;Bernut, Audrey;Arthur, Michel
目的：两种β-内酰胺类药物，头孢西丁和亚胺培南，是肺部脓肿分枝杆菌感染参考治疗的一部分。脓肿分支杆菌最近被证明产生一种广谱的β-内酰胺酶Bla(Mab)，这表明β-内酰胺类药物与Bla(Mab)抑制剂的结合可能会提高治疗效果。本研究的目的是评价Bla(Mab)的产生对体外β-内酰胺类抗生素疗效的影响，以及在细胞内和动物模型中抑制Bla(Mab)对β-内酰胺类抗生素活性的好处。方法：我们分析了目前处于开发第三阶段的非β-内酰胺酶抑制剂Avibactam与头孢他啶联合治疗革兰阴性菌严重感染的Bla(Mab)失活的机制和动力学。然后，我们删除了编码Bla(Mab)的基因，以评估阿维巴坦对Bla(Mab)的抑制程度，这是基于化学灭活和遗传灭活的影响的比较。最后，在培养的人巨噬细胞和感染脓肿支原体的斑马鱼模型中，评估了阿莫西林和阿维巴坦的疗效。结果：我们发现阿莫西林通过可逆地形成共价加合物，有效地灭活了Bla(Mab)。在感染的巨噬细胞和斑马鱼中都观察到了阿维巴坦对Bla(Mab)的抑制作用。结论：我们的数据证实了阿维巴坦是Bla(Mab)的第一有效抑制剂，并强烈建议对β-内酰胺酶抑制进行评估，以提供更好的治疗脓肿分支杆菌感染的选择。
Objectives: Two beta-lactams, cefoxitin and imipenem, are part of the reference treatment for pulmonary infections with Mycobacterium abscessus. M. abscessus has recently been shown to produce a broad-spectrum beta-lactamase, Bla(Mab), indicating that the combination of beta-lactams with a Bla(Mab) inhibitor may improve treatment efficacy. The objectives of this study were to evaluate the impact of Bla(Mab) production on the efficacy of beta-lactams in vitro and to assess the benefit of Bla(Mab) inhibition on the activity of beta-lactams intracellularly and in an animal model.Methods: We analysed the mechanism and kinetics of Bla(Mab) inactivation by avibactam, a non-beta-lactam beta-lactamase inhibitor currently in Phase III of development, in combination with ceftazidime for the treatment of serious infections due to Gram-negative bacteria. We then deleted the gene encoding Bla(Mab) to assess the extent of Bla(Mab) inhibition by avibactam based on a comparison of the impact of chemical and genetic inactivation. Finally, the efficacy of amoxicillin in combination with avibactam was evaluated in cultured human macrophages and in a zebrafish model of M. abscessus infection.Results: We showed that avibactam efficiently inactivated Bla(Mab) via the reversible formation of a covalent adduct. An inhibition of Bla(Mab) by avibactam was observed in both infected macrophages and zebrafish.Conclusions: Our data identify avibactam as the first efficient inhibitor of Bla(Mab) and strongly suggest that beta-lactamase inhibition should be evaluated to provide improved therapeutic options for M. abscessus infections.