期刊
ACS INFECTIOUS DISEASES
卷 3, 期 10, 页码 711-717出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.7b00094
关键词
antibiotic resistance; metallo-beta-lactamase; MBL inhibitor; zinc binding; synergy
资金
- Utrecht University
- Netherlands Organization for Scientific Research (VIDI)
The prevalence of infections caused by metallo-beta-lactamase (MBL) expressing Gram-negative bacteria has grown at an alarming rate in recent years. Despite the fact that MBLs can deactivate virtually all beta-lactam antibiotics, there are as of yet no approved drugs available that inhibit their activity. We here examine the ability of previously reported thiol-based MBL inhibitors to synergize with meropenem and cefoperazone against a panel of Gram-negative carbapenem-resistant isolates expressing different beta-lactamases. Among the compounds tested, thiomandelic acid 3 and 2-mercapto-3-phenylpropionic acid 4 were found to efficiently potentiate the activity of meropenem, especially against an imipenemase (IMP) producing strain of K. pneumoniae. In light of the zinc-dependent hydrolytic mechanism employed by MBLs, biophysical studies using isothermal titration calorimetry were also performed, revealing a correlation between the synergistic activity of thiols 3 and 4 and their zinc-binding ability with measured K-d values of 9.8 and 20.0 mu M, respectively.
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