Louis Stokes Cleveland Veterans Affairs Medical Center Research Service, Cleveland, Ohio, USA.
Department of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
mBio. 2019 Mar 12;10(2):e00159-19. doi: 10.1128/mBio.00159-19.
Multidrug-resistant (MDR) spp. poses a significant therapeutic challenge in part due to the presence of chromosomally encoded β-lactamases, including class C -derived cephalosporinases (ADC) and class D oxacillinases (OXA), as well as plasmid-mediated class A β-lactamases. Importantly, OXA-like β-lactamases represent a gap in the spectrum of inhibition by recently approved β-lactamase inhibitors such as avibactam and vaborbactam. ETX2514 is a novel, rationally designed, diazabicyclooctenone inhibitor that effectively targets class A, C, and D β-lactamases. We show that addition of ETX2514 significantly increased the susceptibility of clinical isolates to sulbactam. AdeB and AdeJ were identified to be key efflux constituents for ETX2514 in The combination of sulbactam and ETX2514 was efficacious against carrying , , , and in a neutropenic murine thigh infection model. We also show that, , ETX2514 inhibited ADC-7 (/ 1.0 ± 0.1 × 10 M s) and OXA-58 (/ 2.5 ± 0.3 × 10 M s). Cocrystallization of ETX2514 with OXA-24/40 revealed hydrogen bonding interactions between ETX2514 and residues R261, S219, and S128 of OXA-24/40 in addition to a chloride ion occupied in the active site. Further, the C3 methyl group of ETX2514 shifts the position of M223. In conclusion, the sulbactam-ETX2514 combination possesses a broadened inhibitory range to include class D β-lactamases as well as class A and C β-lactamases and is a promising therapeutic candidate for infections caused by MDR spp. The number and diversity of β-lactamases are steadily increasing. The emergence of β-lactamases that hydrolyze carbapenems poses a significant threat to our antibiotic armamentarium. The explosion of OXA enzymes that are carbapenem hydrolyzers is a major challenge (carbapenem-hydrolyzing class D [CHD]). An urgent need exists to discover β-lactamase inhibitors with class D activity. The sulbactam-ETX2514 combination demonstrates the potential to become a treatment regimen of choice for spp. producing class D β-lactamases.
多药耐药（MDR） spp. 由于存在染色体编码的β-内酰胺酶，包括 C 类衍生的头孢菌素酶（ADC）和 D 类的苯唑西林酶（OXA），以及质粒介导的 A 类β-内酰胺酶，因此在治疗上构成了重大挑战。重要的是，OXA 样β-内酰胺酶代表了最近批准的β-内酰胺酶抑制剂（如阿维巴坦和沃博巴坦）抑制谱的一个空白。ETX2514 是一种新型的、经过合理设计的二氮杂二环辛酮抑制剂，可有效靶向 A、C 和 D 类β-内酰胺酶。我们表明，添加 ETX2514 可显著提高临床分离株对舒巴坦的敏感性。AdeB 和 AdeJ 被鉴定为 ETX2514 在 中的关键外排成分。在中性粒细胞减少症小鼠大腿感染模型中，舒巴坦和 ETX2514 的联合用药对携带 blaADC-7、blaCTX-M-15、blaOXA-1 和 blaOXA-48 的 有效。我们还表明，ETX2514 抑制 ADC-7（/ 1.0 ± 0.1 × 10 M s）和 OXA-58（/ 2.5 ± 0.3 × 10 M s）。ETX2514 与 OXA-24/40 的共结晶揭示了 ETX2514 与 OXA-24/40 的残基 R261、S219 和 S128 之间的氢键相互作用，以及占据活性位点的氯离子。此外，ETX2514 的 C3 甲基使 M223 的位置发生移动。总之，舒巴坦-ETX2514 联合用药具有更广泛的抑制范围，包括 D 类β-内酰胺酶以及 A 类和 C 类β-内酰胺酶，是治疗 MDR spp. 感染的有前途的治疗候选药物。β-内酰胺酶的数量和多样性正在稳步增加。能够水解碳青霉烯类抗生素的β-内酰胺酶的出现对我们的抗生素武器库构成了重大威胁。碳青霉烯水解酶 OXA 酶的爆发是一个主要挑战（碳青霉烯水解酶 D 类 [CHD]）。迫切需要发现具有 D 类活性的β-内酰胺酶抑制剂。舒巴坦-ETX2514 联合用药具有成为治疗产 D 类β-内酰胺酶 spp. 的首选治疗方案的潜力。
