Zinc Chelator N,N,N′,N′-Tetrakis(2-Pyridylmethyl)Ethylenediamine Reduces the Resistance of Mycobacterium abscessus to Imipenem
Zinc Chelator N,N,N′,N′-Tetrakis(2-Pyridylmethyl)Ethylenediamine Reduces the Resistance of Mycobacterium abscessus to Imipenem
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锌螯合剂N,N,N-2,N-2-四(2-吡啶甲基)乙二胺降低脓肿分枝杆菌对亚胺培南的耐药性
DOI：
10.2147/idr.s267552
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发表时间：
2020-01-01
影响因子：
3.9
通讯作者：
Chu, Haiqing
中科院分区：
文献类型：
--
作者：
He, Siyuan;Zou, Yuzhen;Chu, Haiqing
目的：亚胺培南是治疗脓肿分枝杆菌（M. abscessus）感染极少数有效的选择之一；亚胺培南耐药性的产生是一个重大的健康问题。
材料与方法：测定了194株临床脓肿分枝杆菌分离株对亚胺培南的敏感性。还评估了亚胺培南与N,N,N',N' - 四（2 - 吡啶甲基）乙二胺（TPEN，一种锌螯合剂和金属β - 内酰胺酶（MBLs）抑制剂）协同抑制脓肿分枝杆菌生长的能力。
结果：脓肿分枝杆菌对亚胺培南表现出较高的耐药性（MIC50 = 16毫克/升，MIC90 = 64毫克/升）。TPEN和亚胺培南联合对100%的亚胺培南耐药株和79.2%的亚胺培南中介耐药株的生长具有协同抑制作用；在治疗亚胺培南敏感株时未观察到协同作用。当亚胺培南与TPEN联合时，其MIC50（从16毫克/升降至4毫克/升）和MIC90（从64毫克/升降至8毫克/升）显著降低；亚胺培南耐药株的比例也降低（从48.4%降至0%）。与这些显示协同作用的结果一致，时间 - 杀菌试验表明，添加TPEN显著提高了亚胺培南对脓肿分枝杆菌的杀菌活性。同样，EDTA（一种有效的MBLs抑制剂）在纸片扩散试验中提高了亚胺培南的抗脓肿分枝杆菌活性，证实了TPEN的作用，并支持了MBLs在一些分离株所表现出的亚胺培南耐药性中的作用。
结论：这些研究结果表明，TPEN可以降低脓肿分枝杆菌对亚胺培南的耐药性，并提示抑制MBLs活性是其潜在机制。
Purpose Imipenem is one of the very few effective options for treating Mycobacterium abscessus (M. abscessus) infections; the development of imipenem resistance is a major health concern. Materials and Methods The susceptibility of 194 clinical M. abscessus isolates to imipenem was determined. The ability of imipenem to synergize with N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), a zinc chelator and a metallo-β-lactamases (MBLs) inhibitor, to inhibit M. abscessus growth was also assessed. Results M. abscessus exhibited an elevated resistance to imipenem (MIC50 = 16 mg/L, MIC90 = 64 mg/L). A combination of TPEN and imipenem synergized to inhibit the growth of 100% of imipenem-resistant and 79.2% of imipenem-resistance intermediate isolates; no synergy was observed treating imipenem-sensitive isolates. A remarkable decrease in the MIC50 (from 16 to 4 mg/L) and MIC90 (from 64 to 8 mg/L) of imipenem was observed when it was combined with TPEN; the portion of imipenem-resistant isolates also decreased (from 48.4% to 0%). Consistent with these results demonstrating synergy, a time-kill assay showed the addition of TPEN significantly improved the bactericidal activity of imipenem toward M. abscessus. Similarly, EDTA (a potent MBLs inhibitor) promoted the anti-M. abscessus activity of imipenem in a disk assay, corroborating the effect of TPEN and supporting the role of MBLs in imipenem resistance exhibited by some isolates. Conclusion These findings demonstrate that TPEN can reduce the resistance of M. abscessus to imipenem and suggest that the inhibition of MBLs activity is the underlying mechanism.