Servicio de Microbiología-Instituto de Investigación Biomédica (INIBIC), Complexo Hospitalario Universitario A Coruña, A Coruña, Spain.
Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS) and Departamento de Química Orgánica, Universidade de Santiago de Compostela, Santiago de Compostela, Spain.
Antimicrob Agents Chemother. 2017 Oct 24;61(11). doi: 10.1128/AAC.01172-17. Print 2017 Nov.
The number of infections caused by Gram-negative pathogens carrying carbapenemases is increasing, and the group of carbapenem-hydrolyzing class D β-lactamases (CHDLs) is especially problematic. Several clinically important CHDLs have been identified in , including OXA-23, OXA-24/40, OXA-58, OXA-143, OXA-235, and the chromosomally encoded OXA-51. The selection and dissemination of carbapenem-resistant strains constitutes a serious global threat. Carbapenems have been successfully utilized as last-resort antibiotics for the treatment of multidrug-resistant infections. However, the spread of OXA carbapenemases is compromising the continued use of these antimicrobials. In response to this clinical issue, it is necessary and urgent to design and develop new specific inhibitors with efficacy against these enzymes. The aim of this work was to characterize the inhibitory activity of LN-1-255 (a 6-alkylidene-2-substituted penicillin sulfone) and compare it to that of two established inhibitors (avibactam and tazobactam) against the most relevant enzymes of each group of class D carbapenemases in The β-lactamase inhibitor LN-1-255 demonstrated excellent microbiological synergy and inhibition kinetics parameters against all tested CHDLs and a significantly higher activity than tazobactam and avibactam. A combination of carbapenems and LN-1-255 was effective against class D carbapenemases. Docking assays confirmed the affinity of LN-1-255 for the active site of these enzymes. LN-1-255 represents a potential new β-lactamase inhibitor that may have a significant role in eradicating infections caused by isolates carrying CHDLs.
携带碳青霉烯酶的革兰氏阴性病原体引起的感染数量正在增加，其中碳青霉烯水解酶 D 类β-内酰胺酶（CHDLs）组尤其成问题。在 中已经鉴定出几种临床上重要的 CHDLs，包括 OXA-23、OXA-24/40、OXA-58、OXA-143、OXA-235 和染色体编码的 OXA-51。碳青霉烯耐药 菌株的选择和传播构成了严重的全球威胁。碳青霉烯类抗生素已成功用作治疗多重耐药 感染的最后手段抗生素。然而，OXA 碳青霉烯酶的传播正在危及这些抗菌药物的持续使用。针对这一临床问题，有必要和迫切需要设计和开发针对这些酶具有疗效的新型特异性抑制剂。本工作的目的是研究 6-亚烷基-2-取代青霉素磺酰胺类化合物 LN-1-255 的抑制活性，并将其与两种已建立的抑制剂（阿维巴坦和他唑巴坦）对 中 D 类碳青霉烯酶各组中最相关的酶进行比较。β-内酰胺酶抑制剂 LN-1-255 对所有测试的 CHDL 均表现出优异的微生物协同作用和抑制动力学参数，其活性明显高于他唑巴坦和阿维巴坦。碳青霉烯类药物与 LN-1-255 的联合使用对 类碳青霉烯酶有效。对接试验证实了 LN-1-255 与这些酶的活性位点的亲和力。LN-1-255 代表一种有潜力的新型β-内酰胺酶抑制剂，可能在根除携带 CHDL 的 引起的感染方面发挥重要作用。
