Department of Medicinal Chemistry, University of Minnesota, 308 Harvard St SE, Minneapolis, Minnesota 55455, United States.
ACS Infect Dis. 2022 Oct 14;8(10):1992-2018. doi: 10.1021/acsinfecdis.2c00315. Epub 2022 Sep 1.
The discovery of β-lactam (BL) antibiotics in the early 20th century represented a remarkable advancement in human medicine, allowing for the widespread treatment of infectious diseases that had plagued humanity throughout history. Yet, this triumph was followed closely by the emergence of β-lactamase (BLase), a bacterial weapon to destroy BLs. BLase production is a primary mechanism of resistance to BL antibiotics, and the spread of new homologues with expanded hydrolytic activity represents a pressing threat to global health. Nonetheless, researchers have developed strategies that take advantage of this defense mechanism, exploiting BLase activity in the creation of probes, diagnostic tools, and even novel antibiotics selective for resistant organisms. Early discoveries in the 1960s and 1970s demonstrating that certain BLs expel a leaving group upon BLase cleavage have spawned an entire field dedicated to employing this selective release mechanism, termed BLase-mediated fragmentation. Chemical probes have been developed for imaging and studying BLase-expressing organisms in the laboratory and diagnosing BL-resistant infections in the clinic. Perhaps most promising, new antibiotics have been developed that use BLase-mediated fragmentation to selectively release cytotoxic chemical "warheads" at the site of infection, reducing off-target effects and allowing for the repurposing of putative antibiotics against resistant organisms. This Review will provide some historical background to the emergence of this field and highlight some exciting recent reports that demonstrate the promise of this unique release mechanism.
β-内酰胺（BL）抗生素在 20 世纪初的发现代表了人类医学的重大进步，使得广泛治疗一直困扰人类历史的传染病成为可能。然而，这一胜利之后紧跟着出现了β-内酰胺酶（BLase），这是一种破坏 BL 的细菌武器。BLase 的产生是对 BL 抗生素产生耐药性的主要机制，具有扩展水解活性的新同源物的传播对全球健康构成了紧迫威胁。尽管如此，研究人员已经开发出利用这种防御机制的策略，利用 BLase 的活性来创建探针、诊断工具，甚至是对耐药生物具有选择性的新型抗生素。早在 20 世纪 60 年代和 70 年代的早期发现表明，某些 BL 在 BLase 切割时会排出一个离去基团，这催生了一个专门研究这种选择性释放机制的领域，称为 BLase 介导的片段化。化学探针已经被开发出来，用于在实验室中对表达 BLase 的生物进行成像和研究，并在临床上诊断 BL 耐药感染。也许最有前途的是，已经开发出了使用 BLase 介导的片段化选择性释放细胞毒性化学“弹头”的新型抗生素，从而减少了脱靶效应，并允许针对耐药生物重新利用潜在的抗生素。这篇综述将提供该领域出现的一些历史背景，并重点介绍一些令人兴奋的最新报告，这些报告展示了这种独特释放机制的前景。
