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Inhibition of metallo-beta-lactamases (MBLs) to fight the bacterial resistance to beta-lactam antibiotics.
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International audience. Bacterial resistance to antibiotics is a highly worrying threats to public health and the risk of return to the pre-penicillin era is real. In 2017, WHO has published a Global priority list of antibiotic-resistant bacteria to fight and placed carbapenem-resistant Gram-negative bacteria first.(a) The main mode of resistance to the β-lactam antibiotics Carbapenems, which are last-resort antibiotics at hospital, is the production of β-lactamases, among which the class of metallo-β-lactamases (MBLs) is of extreme concern. One major approach to fight this resistance consists of combination therapy in which a β-lactam antibiotic is given along with a β-lactamase inhibitor, which protects the former from inactivation. Although numerous series of MBL inhibitors have been developed, there are no MBL inhibitors marketed yet. In 2008, the crystallographic structure of the MBL L1 with compound IIIA (2HB9.pdb) revealed the original binding mode of the triazole-thione scaffold, which simultaneously coordinates the two zinc atoms in the enzyme active site (figure 1).(b) Since then, our laboratory developed various series based on this scaffold.(c),(d) Among these, several compounds were found to inhibit several important MBLs (NDM- and VIM-types) with Ki in the M to sub-M range. In addition, some compounds were shown to restore the susceptibility of MBL-producing clinical strains to meropenem. Finally, the resolution of the crystallographic 3D structure of VIM-2 in complex with one inhibitor confirmed the binding mode of these compounds.We will present and discuss the synthesis and biological evaluation of triazole-thione-based MBLs inhibitors.
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