PreprintArticleVersion 1Preserved in Portico This version is not peer-reviewed
Potent Inhibitors Targeting Metallo-β-lactamases from the B1, B2 and B3 Subgroups: Promising Broad-spectrum Agents to Combat a Major Mechanism of Antibiotic Resistance
Version 1
: Received: 30 March 2023 / Approved: 31 March 2023 / Online: 31 March 2023 (03:35:02 CEST)
How to cite:
Kurz, J.L.; Pedroso, M.M.; Richard, E.; McGeary, R.P.; Schenk, G. Potent Inhibitors Targeting Metallo-β-lactamases from the B1, B2 and B3 Subgroups: Promising Broad-spectrum Agents to Combat a Major Mechanism of Antibiotic Resistance. Preprints2023, 2023030539. https://doi.org/10.20944/preprints202303.0539.v1
Kurz, J.L.; Pedroso, M.M.; Richard, E.; McGeary, R.P.; Schenk, G. Potent Inhibitors Targeting Metallo-β-lactamases from the B1, B2 and B3 Subgroups: Promising Broad-spectrum Agents to Combat a Major Mechanism of Antibiotic Resistance. Preprints 2023, 2023030539. https://doi.org/10.20944/preprints202303.0539.v1
Kurz, J.L.; Pedroso, M.M.; Richard, E.; McGeary, R.P.; Schenk, G. Potent Inhibitors Targeting Metallo-β-lactamases from the B1, B2 and B3 Subgroups: Promising Broad-spectrum Agents to Combat a Major Mechanism of Antibiotic Resistance. Preprints2023, 2023030539. https://doi.org/10.20944/preprints202303.0539.v1
APA Style
Kurz, J.L., Pedroso, M.M., Richard, E., McGeary, R.P., & Schenk, G. (2023). Potent Inhibitors Targeting Metallo-β-lactamases from the B1, B2 and B3 Subgroups: Promising Broad-spectrum Agents to Combat a Major Mechanism of Antibiotic Resistance. Preprints. https://doi.org/10.20944/preprints202303.0539.v1
Chicago/Turabian Style
Kurz, J.L., Ross P McGeary and Gerhard Schenk. 2023 "Potent Inhibitors Targeting Metallo-β-lactamases from the B1, B2 and B3 Subgroups: Promising Broad-spectrum Agents to Combat a Major Mechanism of Antibiotic Resistance" Preprints. https://doi.org/10.20944/preprints202303.0539.v1
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 representatives of each of the three subgroups of MBLs (B1, B2, B3). Several compounds are potent inhibitors of each MBL tested, making them excellent candidates for the development of broad-spectrum drug leads. In particular, compound 5f is highly potent across the MBL subfamilies, with Ki values in the low µM range. Furthermore, this compound also dis-plays synergy in combination with antibiotics such as penicillin G, cefuroxime or meropenem. This molecule thus represents one of the most promising compounds developed yet to combat MBLs.
Chemistry and Materials Science, Medicinal Chemistry
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
