设计、合成及对金属β-内酰胺酶 IMP-1 具有高抑制活性的氨基酸衍生硫醇抑制剂的体外和生物学评价。
Design, synthesis, and in vitro and biological evaluation of potent amino acid-derived thiol inhibitors of the metallo-β-lactamase IMP-1.
机构信息
The University of Queensland, School of Chemistry and Molecular Biosciences, Brisbane, Qld, 4072, Australia.
The University of Queensland, School of Chemistry and Molecular Biosciences, Brisbane, Qld, 4072, Australia; Helwan University, Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Ein Helwan, Helwan, Egypt.
出版信息
Eur J Med Chem. 2016 May 23;114:318-27. doi: 10.1016/j.ejmech.2016.03.017. Epub 2016 Mar 9.
There are currently no clinically available inhibitors of metallo-β-lactamases (MBLs). These enzymes confer resistance to bacteria against a broad range of commonly used β-lactam antibiotics, and are produced by an increasing number of bacterial pathogens. In this study, several thiol derivatives of l-amino acids were designed and synthesized, and their inhibitory effects against the metallo-β-lactamase IMP-1 (subclass B1) were investigated. The most potent compound, derived from l-tyrosine, exhibited competitive inhibition, with a Ki of 86 nM. The ability of this compound to render MBL-expressing bacteria susceptible to imipenem was examined. Reductions in MIC values up to 5.2-fold were observed.
目前尚无临床可用的金属β-内酰胺酶（MBLs）抑制剂。这些酶使细菌对广泛使用的β-内酰胺类抗生素产生耐药性，并且越来越多的细菌病原体产生这些酶。在这项研究中，设计和合成了几种 l-氨基酸的硫醇衍生物，并研究了它们对金属β-内酰胺酶 IMP-1（B1 亚类）的抑制作用。最有效的化合物来源于 l-酪氨酸，表现出竞争性抑制作用，Ki 值为 86 nM。研究了该化合物使产 MBL 的细菌对亚胺培南敏感的能力。观察到 MIC 值降低了 5.2 倍。
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