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Thiol-Containing Metallo-?-Lactamase Inhibitors Resensitize Resistant Gram-Negative Bacteria to Meropenem.


ABSTRACT: The prevalence of infections caused by metallo-?-lactamase (MBL) expressing Gram-negative bacteria has grown at an alarming rate in recent years. Despite the fact that MBLs can deactivate virtually all ?-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 ?-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 Kd values of 9.8 and 20.0 ?M, respectively.

SUBMITTER: Tehrani KHME 

PROVIDER: S-EPMC5644712 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Thiol-Containing Metallo-β-Lactamase Inhibitors Resensitize Resistant Gram-Negative Bacteria to Meropenem.

Tehrani Kamaleddin Haj Mohammad Ebrahim KHME   Martin Nathaniel I NI  

ACS infectious diseases 20170828 10


The prevalence of infections caused by metallo-β-lactamase (MBL) expressing Gram-negative bacteria has grown at an alarming rate in recent years. Despite the fact that MBLs can deactivate virtually all β-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 di  ...[more]

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