2. Academic Validation
  3. N-Aryl Mercaptopropionamides as Broad-Spectrum Inhibitors of Metallo-β-Lactamases

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

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%.

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