ZN148 Is a Modular Synthetic Metallo-beta-Lactamase Inhibitor That Reverses Carbapenem Resistance in Gram-Negative Pathogens In Vivo
| Autor: | Christian Schnaars, Adriana Magalhaes Santos Andresen, Silje Lauksund, Christopher Fröhlich, Pal Rongved, Ole Andreas Økstad, Sandra Huber, Susann Skagseth, Tor Gjøen, Ørjan Samuelsen, Adam Heikal, Hanna-Kirsti S. Leiros, Ove Alexander Høgmoen Åstrand, Annette Bayer, Geir Kildahl-Andersen, Trine Josefine Olsen Carlsen, Sarah Finke |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Carbapenem
antibiotic resistance Klebsiella pneumoniae metallo-β-lactamase VDP::Matematikk og Naturvitenskap: 400::Basale biofag: 470::Generell mikrobiologi: 472 chemical and pharmacologic phenomena β-lactamases VDP::Medical disciplines: 700::Clinical medical disciplines: 750::Communicable diseases: 776 Meropenem beta-Lactam Resistance beta-Lactamases Microbiology carbapenem 03 medical and health sciences Mice Antibiotic resistance VDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Infeksjonsmedisin: 776 In vivo medicine polycyclic compounds β-lactamase inhibitor Animals Pharmacology (medical) Experimental Therapeutics 030304 developmental biology Pharmacology chemistry.chemical_classification 0303 health sciences biology 030306 microbiology VDP::Mathematics and natural science: 400::Basic biosciences: 470::General microbiology: 472 biochemical phenomena metabolism and nutrition biology.organism_classification bacterial infections and mycoses Acute toxicity In vitro Anti-Bacterial Agents Infectious Diseases Enzyme chemistry Carbapenems bacteria beta-Lactamase Inhibitors medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy |
| ISSN: | 0066-4804 |
| Popis: | Carbapenem-resistant Gram-negative pathogens are a critical public health threat and there is an urgent need for new treatments. Carbapenemases (β-lactamases able to inactivate carbapenems) have been identified in both serine β-lactamase (SBL) and metallo-β-lactamase (MBL) families. The recent introduction of SBL carbapenemase inhibitors has provided alternative therapeutic options. Unfortunately, there are no approved inhibitors of MBL-mediated carbapenem-resistance and treatment options for infections caused by MBL-producing Gram-negatives are limited. Carbapenem-resistant Gram-negative pathogens are a critical public health threat and there is an urgent need for new treatments. Carbapenemases (β-lactamases able to inactivate carbapenems) have been identified in both serine β-lactamase (SBL) and metallo-β-lactamase (MBL) families. The recent introduction of SBL carbapenemase inhibitors has provided alternative therapeutic options. Unfortunately, there are no approved inhibitors of MBL-mediated carbapenem-resistance and treatment options for infections caused by MBL-producing Gram-negatives are limited. Here, we present ZN148, a zinc-chelating MBL-inhibitor capable of restoring the bactericidal effect of meropenem and in vitro clinical susceptibility to carbapenems in >98% of a large international collection of MBL-producing clinical Enterobacterales strains (n = 234). Moreover, ZN148 was able to potentiate the effect of meropenem against NDM-1-producing Klebsiella pneumoniae in a murine neutropenic peritonitis model. ZN148 showed no inhibition of the human zinc-containing enzyme glyoxylase II at 500 μM, and no acute toxicity was observed in an in vivo mouse model with cumulative dosages up to 128 mg/kg. Biochemical analysis showed a time-dependent inhibition of MBLs by ZN148 and removal of zinc ions from the active site. Addition of exogenous zinc after ZN148 exposure only restored MBL activity by ∼30%, suggesting an irreversible mechanism of inhibition. Mass-spectrometry and molecular modeling indicated potential oxidation of the active site Cys221 residue. Overall, these results demonstrate the therapeutic potential of a ZN148-carbapenem combination against MBL-producing Gram-negative pathogens and that ZN148 is a highly promising MBL inhibitor that is capable of operating in a functional space not presently filled by any clinically approved compound. |
| Databáze: | OpenAIRE |
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