Dipartimento di Scienze Chimiche, Università degli Studi di Catania, V.le A. Doria 6, 95125 Catania, Italy.
Clinical Microbiology and Virology Unit, A. Manzoni Hospital, Via dell'Eremo 9/11, 23900 Lecco, Italy.
J Inorg Biochem. 2021 Feb;215:111315. doi: 10.1016/j.jinorgbio.2020.111315. Epub 2020 Nov 21.
Bacteria have developed multiple resistance mechanisms against the most used antibiotics. In particular, zinc-dependent metallo-β-lactamase producing bacteria are a growing threat, and therapeutic options are limited. Zinc chelators have recently been investigated as metallo-β-lactamase inhibitors, as they are often able to restore carbapenem susceptibility. We synthesized polypyridyl ligands, N,N'-bis(2-pyridylmethyl)-ethylenediamine, N,N,N'-tris(2-pyridylmethyl)-ethylenediamine, N,N'-bis(2-pyridylmethyl)-ethylenediamine-N-acetic acid (N,N,N'-tris(2-pyridylmethyl)-ethylenediamine-N'-acetic acid, which can form zinc(II) complexes. We tested their ability to restore the antibiotic activity of meropenem against three clinical strains isolated from blood and metallo-β-lactamase producers (Klebsiella pneumoniae, Enterobacter cloacae, and Stenotrophomonas maltophilia). We functionalized N,N,N'-tris(2-pyridylmethyl)-ethylenediamine with D-alanyl-D-alanyl-D-alanine methyl ester with the aim to increase bacterial uptake. We observed synergistic activity of four polypyridyl ligands with meropenem against all tested isolates, while the combination N,N'-bis(2-pyridylmethyl)-ethylenediamine and meropenem was synergistic only against New Delhi and Verona integron-encoded metallo-β-lactamase-producing bacteria. All synergistic interactions restored the antimicrobial activity of meropenem, providing a significant decrease of minimal inhibitory concentration value (by 8- to 128-fold). We also studied toxicity of the ligands in two normal peripheral blood lymphocytes.
细菌已经针对最常用的抗生素开发了多种耐药机制。特别是，产生锌依赖性金属β-内酰胺酶的细菌是一个日益严重的威胁，治疗选择有限。锌螯合剂最近已被研究作为金属β-内酰胺酶抑制剂，因为它们通常能够恢复碳青霉烯类药物的敏感性。我们合成了多吡啶配体，N,N'-双（2-吡啶甲基）-乙二胺，N,N,N'-三（2-吡啶甲基）-乙二胺，N,N'-双（2-吡啶甲基）-乙二胺-N-乙酸（N,N,N'-三（2-吡啶甲基）-乙二胺-N'-乙酸，它们可以形成锌（II）配合物。我们测试了它们恢复美罗培南对三种从血液中分离出的临床菌株和金属β-内酰胺酶产生菌（肺炎克雷伯菌、阴沟肠杆菌和嗜麦芽寡养单胞菌）的抗生素活性的能力。我们用 D-丙氨酰-D-丙氨酰-D-丙氨酸甲酯对 N,N,N'-三（2-吡啶甲基）-乙二胺进行了功能化，目的是增加细菌摄取。我们观察到四种多吡啶配体与美罗培南对所有测试分离株均具有协同作用，而 N,N'-双（2-吡啶甲基）-乙二胺和美罗培南的组合仅对新德里和维罗纳整合子编码的金属β-内酰胺酶产生菌具有协同作用。所有协同相互作用都恢复了美罗培南的抗菌活性，使最小抑菌浓度值显著降低（降低 8 至 128 倍）。我们还在两种正常外周血淋巴细胞中研究了配体的毒性。
