Suppression of β-Lactam Resistance by Aspergillomarasmine A Is Influenced by both the Metallo-β-Lactamase Target and the Antibiotic Partner.

Autor:	Rotondo CM; David Braley Centre for Antibiotic Discovery, McMaster University, Hamilton, Ontario, Canada.; M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada., Sychantha D; David Braley Centre for Antibiotic Discovery, McMaster University, Hamilton, Ontario, Canada.; M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada., Koteva K; David Braley Centre for Antibiotic Discovery, McMaster University, Hamilton, Ontario, Canada.; M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada., Wright GD; David Braley Centre for Antibiotic Discovery, McMaster University, Hamilton, Ontario, Canada wrightge@mcmaster.ca.; M.G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2020 Mar 24; Vol. 64 (4). Date of Electronic Publication: 2020 Mar 24 (Print Publication: 2020).
DOI:	10.1128/AAC.01386-19
Abstrakt:	The rise of Gram-negative pathogens expressing metallo-β-lactamases (MBLs) is a growing concern, threatening the efficacy of β-lactam antibiotics, in particular, the carbapenems. There are no inhibitors of MBLs in current clinical use. Aspergillomarasmine A (AMA) is an MBL inhibitor isolated from Aspergillus versicolor with the ability to rescue meropenem activity in MBL-producing bacteria both in vitro and in vivo Here, we systematically explored the pairing of AMA with six β-lactam antibiotic partners against 19 MBLs from three subclasses (B1, B2, and B3). Cell-based assays performed with Escherichia coli and Klebsiella pneumoniae showed that bacteria producing NDM-1 and VIM-2 of subclass B1 were the most susceptible to AMA inhibition, whereas bacteria producing CphA2 and AIM-1 of subclasses B2 and B3, respectively, were the least sensitive. Intracellular antibiotic accumulation assays and in vitro enzyme assays demonstrated that the efficacy of AMA/β-lactam combinations did not correlate with outer membrane permeability or drug efflux. We determined that the optimal β-lactam partners for AMA are the carbapenem antibiotics and that the efficacy of AMA is linked to the Zn 2+ affinity of specific MBLs. (Copyright © 2020 American Society for Microbiology.)
Databáze:	MEDLINE
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