N-Aryl Mercaptopropionamides as Broad-Spectrum Inhibitors of Metallo-β-Lactamases

  • J Med Chem. 2022 Mar 10;65(5):3913-3922. doi: 10.1021/acs.jmedchem.1c01755.
Cansu Kaya  1  2 ,  Jelena Konstantinović  1 ,  Andreas M Kany  1 ,  Anastasia Andreas  1  2 ,  Jan S Kramer  3 ,  Steffen Brunst  3 ,  Lilia Weizel  3 ,  Marco J Rotter  3 ,  Denia Frank  4 ,  Samir Yahiaoui  1 ,  Rolf Müller  1  2  5 ,  Rolf W Hartmann  1  2 ,  Jörg Haupenthal  1 ,  Ewgenij Proschak  3 ,  Thomas A Wichelhaus  4 ,  Anna K H Hirsch  1  2  5
Affiliations
  • 1. Helmholtz Institute for Pharmaceutical Research Saarland, (HIPS)─Helmholtz Centre for Infection Research (HZI), Campus E8.1, 66123 Saarbrücken, Germany.
  • 2. Department of Pharmacy, Saarland University, Campus E8.1, 66123 Saarbrücken, Germany.
  • 3. Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Straße 9, 60438 Frankfurt, Germany.
  • 4. Institute of Medical Microbiology and Infection Control, University Hospital Frankfurt, Paul-Ehrlich-Straße 40, 60596 Frankfurt, Germany.
  • 5. Helmholtz International Lab for Anti-infectives, Campus E8.1, 66123 Saarbrücken, Germany.
PMID: 35188771 DOI: 10.1021/acs.jmedchem.1c01755
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%.

Products