<i>N</i>-Aryl Mercaptopropionamides as Broad-Spectrum Inhibitors of Metallo-β-Lactamases
Cansu Kaya, Jelena Konstantinović, Andreas M. Kany, Anastasia Andreas, Jan S. Kramer, Steffen Brunst, Lilia Weizel, M Rotter, Denia Frank, Samir Yahiaoui, Rolf Müller, Rolf W. Hartmann, Jörg Haupenthal, Ewgenij Proschak, Thomas A. Wichelhaus, Anna K. H. Hirsch
Abstract
Drug-resistant pathogens pose a global challenge to public health as they cause diseases that are extremely difficult to cure. Metallo-β-lactamases (MBLs) are a diverse set of zinc-containing enzymes that catalyze the hydrolysis of β-lactam drugs, including carbapenems, which are considered as the last resort to fight severe infections. To restore the activity of current β-lactam antibiotics and to offer an orthogonal strategy to the discovery of new antibiotics, we have identified a series of polar N-aryl mercaptopropionamide derivatives as potent inhibitors of several class B1 MBLs. We have identified a hit structure with high selectivity restoring the effect of imipenem and reducing minimum inhibitory concentration (MIC) values up to 256-fold in resistant isolates from Escherichia coli. Furthermore, the combination of imipenem with our inhibitor showed in vivo efficacy in a Galleria mellonella model, increasing the survival rate of infected larvae by up to 31%.