鲍曼不动杆菌临床分离株对舒巴坦联合新型β-内酰胺酶抑制剂 ETX2514 自发耐药的频率和机制。
Frequency and Mechanism of Spontaneous Resistance to Sulbactam Combined with the Novel β-Lactamase Inhibitor ETX2514 in Clinical Isolates of Acinetobacter baumannii.
机构信息
Entasis Therapeutics, Waltham, Massachusetts, USA
Entasis Therapeutics, Waltham, Massachusetts, USA.
出版信息
Antimicrob Agents Chemother. 2018 Jan 25;62(2). doi: 10.1128/AAC.01576-17. Print 2018 Feb.
Abstract
The novel diazabicyclooctenone ETX2514 is a potent, broad-spectrum serine β-lactamase inhibitor that restores sulbactam activity against resistant The frequency of spontaneous resistance to sulbactam-ETX2514 in clinical isolates was found to be 7.6 × 10 to <9.0 × 10 at 4× MIC and mapped to residues near the active site of penicillin binding protein 3 (PBP3). Purified mutant PBP3 proteins demonstrated reduced affinity for sulbactam. In a sulbactam-sensitive isolate, resistance also mapped to stringent response genes associated with resistance to PBP2 inhibitors, suggesting that in addition to β-lactamase inhibition, ETX2514 may enhance sulbactam activity in via inhibition of PBP2.
摘要
新型二氮杂二环辛酮 ETX2514 是一种强效、广谱的丝氨酸 β-内酰胺酶抑制剂，可恢复舒巴坦对耐药的活性。在临床分离株中，舒巴坦-ETX2514 自发耐药的频率在 4×MIC 时为 7.6×10 至 <9.0×10，定位于青霉素结合蛋白 3（PBP3）的活性部位附近的残基。纯化的突变 PBP3 蛋白显示对舒巴坦的亲和力降低。在舒巴坦敏感的分离株中，耐药性也定位于与 PBP2 抑制剂耐药相关的严格反应基因，表明除了β-内酰胺酶抑制作用外，ETX2514 还可能通过抑制 PBP2 来增强舒巴坦在 中的活性。
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