Inhibitors for metallo-β-lactamases from the B1 and B3 subgroups provide an avenue to combat a major mechanism of antibiotic resistance

Julia L Kurz; Marcelo Monteiro Pedroso; Emmanuelle Richard; Ross P McGeary; Gerhard Schenk

doi:10.1016/j.bmcl.2023.129387

Inhibitors for metallo-β-lactamases from the B1 and B3 subgroups provide an avenue to combat a major mechanism of antibiotic resistance

Bioorg Med Chem Lett. 2023 Aug 15:92:129387. doi: 10.1016/j.bmcl.2023.129387. Epub 2023 Jun 25.

Authors

Julia L Kurz¹, Marcelo Monteiro Pedroso¹, Emmanuelle Richard¹, Ross P McGeary², Gerhard Schenk³

Affiliations

¹ School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, QLD 4072, Australia.
² School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, QLD 4072, Australia. Electronic address: r.mcgeary@uq.edu.au.
³ School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, QLD 4072, Australia; Australian Centre for Ecogenomics, The University of Queensland, St. Lucia, QLD 4072, Australia; Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St. Lucia, QLD 4072, Australia; Sustainable Minerals Institute, The University of Queensland, St. Lucia, QLD 4072, Australia. Electronic address: schenk@uq.edu.au.

PMID: 37369333
DOI: 10.1016/j.bmcl.2023.129387

Abstract

Metallo-β-lactamases (MBLs) are a group of Zn(II)-dependent enzymes that pose a major threat to global health. They are linked to an increasing number of multi-drug resistant bacterial pathogens, but no clinically useful inhibitor is yet available. Since β-lactam antibiotics, which are inactivated by MBLs, constitute ∼65% of all antibiotics used to treat infections, the search for clinically relevant MBL inhibitors is urgent. Here, derivatives of a 2-amino-1-benzyl-4,5-diphenyl-1H-pyrrole-3-carbonitrile (1a) were synthesised and their inhibitory effects assessed against prominent representatives of the MBL family. Several compounds are potent inhibitors of each MBL tested, making them promising candidates for the development of broad-spectrum drug leads. In particular, compound 5f is highly potent across the MBL family, with K_i values in the low µM range. Furthermore, this compound also appears to display synergy in combination with antibiotics such as penicillin G, cefuroxime or meropenem. This molecule thus represents a promising starting point to develop new drugs to inhibit a major mechanism of antibiotic resistance.

Keywords: Antibiotic resistance; Broad-spectrum inhibitors; Inhibition assays; Metal-dependent enzymes; Metallo-β-lactamases.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / pharmacology
Drug Resistance, Multiple, Bacterial
Meropenem
beta-Lactamase Inhibitors* / pharmacology
beta-Lactamases*

Substances

beta-Lactamases
beta-Lactamase Inhibitors
Anti-Bacterial Agents
Meropenem