In vitro and in vivo activity of ML302F: a thioenolate inhibitor of VIM-subfamily metallo ß-lactamases
In vitro and in vivo activity of ML302F: a thioenolate inhibitor of VIM-subfamily metallo ß-lactamases
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ML302F 的体外和体内活性：VIM 亚家族金属 γ-内酰胺酶的硫代烯醇盐抑制剂
作者：
Betts J
硫烯醇ML302F最近被鉴定为B类金属β-内酰胺酶（MBLs）的抑制剂。我们评估了ML302F与美罗培南（MEM）联合对31株碳青霉烯耐药革兰氏阴性临床分离株的活性。MEM: ML302F的最低抑制浓度以1:4和1:8的固定比例测定，使用产生临床相关vim样MBL变体的菌株。在一种mellonera无脊椎动物模型中，对产生VIM-1、VIM-2和VIM-4变体的菌株进行了体内毒性和有效性评估。在固定的MEM: ML302F比例为1:8时，22/31株菌株对MEM敏感（MIC≤2mg L−1）或中间（MIC 4 - 8mg L−1）。ML302F在高达80 mg kg - 1时对大黄蜂无毒性，MEM 0.6 mg kg - 1和ML302F 4.8 mg kg - 1处理显著提高了受感染幼虫的存活率。由于ML302F能够在体外和体内成功地恢复对耐药菌株的敏感性，因此在寻找新的MBL抑制剂中，它代表了一种结构上有趣的抑制剂。
The thioenol ML302F was recently identified as an inhibitor of class B metallo-β-lactamases (MBLs). We assessed the activity of ML302F when combined with meropenem (MEM) against 31 carbapenem resistant Gram-negative clinical isolates. Minimum inhibitory concentrations of MEM : ML302F were determined at fixed ratios of 1 : 4 and 1 : 8 using strains producing variants of the clinically relevant VIM-like MBL. Toxicity and efficacy in vivo was assessed in a Galleria mellonella invertebrate model against strains producing VIM-1, VIM-2 and VIM-4 variants. At a fixed MEM : ML302F ratio of 1 : 8, 22/31 isolates were rendered either susceptible (MIC ≤ 2 mg L−1), or intermediate (MIC 4–8 mg L−1) to MEM. ML302F alone was not toxic at up to 80 mg kg−1 in G. mellonella and treatment with MEM 0.6 mg kg−1 : ML302F 4.8 mg kg−1 significantly improved the survival of infected larvae. As ML302F was able to successfully restore susceptibility to resistant strains both in vitro and in vivo it represents a structurally interesting inhibitor in the search for new MBL inhibitors.