Design, synthesis, and in vitro and biological evaluation of potent amino acid-derived thiol inhibitors of the metallo-beta-lactamase IMP-1

作者：Arjomandi Omid Khalili; Hussein Waleed M; Vella Peter; Yusof Yusralina; Sidjabat Hanna E; Schenk Gerhard; McGeary Ross P^*

来源：European Journal of Medicinal Chemistry, 2016, 114: 318-327.

DOI：10.1016/j.ejmech.2016.03.017

• Metallo-beta-lactamase
• Enzyme inhibitor
• Antibiotic resistance

There are currently no clinically available inhibitors of metallo-beta-lactamases (MBLs). These enzymes confer resistance to bacteria against a broad range of commonly used beta-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-beta-lactamase IMP-1 (subclass B1) were investigated. The most potent compound, derived from L-tyrosine, exhibited competitive inhibition, with a K-i 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.

• 出版日期2016-5-23