Iyer Ramkumar, Moussa Samir H, Durand-Réville Thomas F, Tommasi Ruben, Miller Alita
Entasis Therapeutics , 35 Gatehouse Drive , Waltham , Massachusetts 02451 , United States.
ACS Infect Dis. 2018 Mar 9;4(3):373-381. doi: 10.1021/acsinfecdis.7b00168. Epub 2017 Dec 26.
OmpA is a conserved, abundantly expressed outer membrane porin in Acinetobacter baumannii whose presumed role in antibiotic permeation has not been clearly demonstrated. In this report, we use a titratable heterologous expression system to express OmpA in isolation and demonstrate selective passage of small molecule antibiotics through OmpA. ETX2514, a recently discovered broad-spectrum β-lactamase inhibitor, in combination with sulbactam, is currently in clinical testing for the treatment of drug-resistant A. baumannii infections. We demonstrate that ETX2514 permeates OmpA and potentiates the activity of sulbactam in an OmpA-dependent manner. In addition, we show that small modifications in the structure of ETX2514 differentially affect its passage through OmpA, revealing unique structure-porin-permeation relationships. Finally, we confirm the contribution of OmpA to bacterial fitness using a murine thigh model of A. baumannii infection. These results, combined with the high sequence homology of OmpA across Acinetobacter spp., suggest that optimization of antibiotic entry through OmpA may prove to be a feasible medicinal chemistry design strategy for future antibacterial discovery efforts.
外膜蛋白A（OmpA）是鲍曼不动杆菌中一种保守且大量表达的外膜孔蛋白，其在抗生素渗透中的假定作用尚未得到明确证实。在本报告中，我们使用一种可滴定的异源表达系统单独表达OmpA，并证明小分子抗生素可通过OmpA进行选择性通透。ETX2514是一种最近发现的广谱β-内酰胺酶抑制剂，与舒巴坦联合使用，目前正处于治疗耐药鲍曼不动杆菌感染的临床试验阶段。我们证明ETX2514可透过OmpA，并以OmpA依赖的方式增强舒巴坦的活性。此外，我们表明ETX2514结构的微小修饰会对其通过OmpA的通透产生不同影响，揭示了独特的结构-孔蛋白-通透关系。最后，我们使用鲍曼不动杆菌感染的小鼠大腿模型证实了OmpA对细菌适应性的贡献。这些结果与不动杆菌属中OmpA的高序列同源性相结合，表明通过优化抗生素通过OmpA的进入可能被证明是未来抗菌药物发现工作中一种可行的药物化学设计策略。
