一种头孢菌素-三足形胺缀合物高效低毒抑制金属β-内酰胺酶。
A Cephalosporin-Tripodalamine Conjugate Inhibits Metallo-β-Lactamase with High Efficacy and Low Toxicity.
机构信息
Institute of Advanced Synthesis, Institute of Chemical Biology and Functional Molecules, School of Chemistry and Molecular Engineering, Nanjing Tech University, Nanjing, China.
Department of Geriatrics, Nanjing Drum Tower Hospitalgrid.428392.6, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
出版信息
Antimicrob Agents Chemother. 2022 Oct 18;66(10):e0035222. doi: 10.1128/aac.00352-22. Epub 2022 Sep 12.
The wide spread of metallo-β-lactamase (MBL)-expressing bacteria has greatly threatened human health, and there is an urgent need for inhibitors against MBLs. Herein, we present a cephalosporin-tripodalamine conjugate (DPASC) as a potent MBL inhibitor with a block-release design. The cephalosporin tag blocks the ligand binding site to reduce toxicity and is cleaved by MBLs to release active ligands to inhibit MBLs . The screening of MBL-expressing pathogenic strains with 16 μg/mL DPASC showed a decrease of the minimum inhibitory concentration of meropenem (MEM) by 16 to 512-fold, and its toxicity was minimal to human HepG2 cells, with an IC exceeding 512 μg/mL. An infection model with Galleria mellonella larvae showed an increased 3-day survival rate of 87% with the coadministration of DPASC and MEM, compared to 50% with MEM alone and no toxicity at a dose of 256 mg/kg of DPASC. Our findings with DPASC demonstrate that it is an effective MBL inhibitor and that the block-release strategy could be useful for the development of new MBL inhibitors.
金属β-内酰胺酶（MBL）表达细菌的广泛传播极大地威胁了人类健康，因此急需开发针对 MBL 的抑制剂。在此，我们提出了一种头孢菌素-三足体胺缀合物（DPASC），它是一种具有阻断释放设计的有效 MBL 抑制剂。头孢菌素标签可阻断配体结合位点以降低毒性，并被 MBL 切割以释放活性配体来抑制 MBL。用 16 μg/mL DPASC 对表达 MBL 的致病性菌株进行筛选，结果显示美罗培南（MEM）的最小抑菌浓度降低了 16 至 512 倍，对人 HepG2 细胞的毒性最小，IC 超过 512 μg/mL。在大蜡螟幼虫感染模型中，与单独使用 MEM 相比，DPASC 和 MEM 联合给药可将 3 天生存率提高至 87%，而 DPASC 剂量为 256 mg/kg 时无毒性。我们的 DPASC 研究结果表明，它是一种有效的 MBL 抑制剂，阻断释放策略可能有助于开发新的 MBL 抑制剂。
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