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Start Over Author "Minerdi, Daniela" Journal antimicrobial agents and chemotherapy
3 results on '"Minerdi, Daniela"'

2. Escherichia coliOverexpressing a Baeyer-Villiger Monooxygenase from Acinetobacter radioresistensBecomes Resistant to Imipenem

Author

Minerdi, Daniela, Zgrablic, Ivan, Castrignanò, Silvia, Catucci, Gianluca, Medana, Claudio, Terlizzi, Maria Elena, Gribaudo, Giorgio, Gilardi, Gianfranco, and Sadeghi, Sheila J.

Abstract

ABSTRACTAntimicrobial resistance is a global issue currently resulting in the deaths of hundreds of thousands of people a year worldwide. Data present in the literature illustrate the emergence of many bacterial species that display resistance to known antibiotics; Acinetobacterspp. are a good example of this. We report here that Acinetobacter radioresistenshas a Baeyer-Villiger monooxygenase (Ar-BVMO) with 100% amino acid sequence identity to the ethionamide monooxygenase of multidrug-resistant (MDR) Acinetobacter baumannii. Both enzymes are only distantly phylogenetically related to other canonical bacterial BVMO proteins. Ar-BVMO not only is capable of oxidizing two anticancer drugs metabolized by human FMO3, danusertib and tozasertib, but also can oxidize other synthetic drugs, such as imipenem. The latter is a member of the carbapenems, a clinically important antibiotic family used in the treatment of MDR bacterial infections. Susceptibility tests performed by the Kirby-Bauer disk diffusion method demonstrate that imipenem-sensitive Escherichia coliBL21 cells overexpressing Ar-BVMO become resistant to this antibiotic. An agar disk diffusion assay proved that when imipenem reacts with Ar-BVMO, it loses its antibiotic property. Moreover, an NADPH consumption assay with the purified Ar-BVMO demonstrates that this antibiotic is indeed a substrate, and its product is identified by liquid chromatography-mass spectrometry to be a Baeyer-Villiger (BV) oxidation product of the carbonyl moiety of the β-lactam ring. This is the first report of an antibiotic-inactivating BVMO enzyme that, while mediating its usual BV oxidation, also operates by an unprecedented mechanism of carbapenem resistance.

Published
2015
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3. Escherichia coli Overexpressing a Baeyer-Villiger Monooxygenase from Acinetobacter radioresistens Becomes Resistant to Imipenem.

Author

Minerdi D, Zgrablic I, Castrignanò S, Catucci G, Medana C, Terlizzi ME, Gribaudo G, Gilardi G, and Sadeghi SJ

Subjects
Acinetobacter classification, Acinetobacter drug effects, Acinetobacter genetics, Anti-Bacterial Agents pharmacology, Antineoplastic Agents metabolism, Bacterial Proteins genetics, Bacterial Proteins metabolism, Benzamides metabolism, Biotransformation, Cloning, Molecular, Disk Diffusion Antimicrobial Tests, Escherichia coli classification, Escherichia coli drug effects, Escherichia coli enzymology, Gene Expression, Imipenem pharmacology, Metabolic Engineering, Mixed Function Oxygenases genetics, Mixed Function Oxygenases metabolism, NADP metabolism, Oxidation-Reduction, Phylogeny, Piperazines metabolism, Pyrazoles metabolism, Recombinant Proteins genetics, Recombinant Proteins metabolism, Acinetobacter enzymology, Anti-Bacterial Agents metabolism, Drug Resistance, Multiple, Bacterial genetics, Escherichia coli genetics, Imipenem metabolism
Abstract

Antimicrobial resistance is a global issue currently resulting in the deaths of hundreds of thousands of people a year worldwide. Data present in the literature illustrate the emergence of many bacterial species that display resistance to known antibiotics; Acinetobacter spp. are a good example of this. We report here that Acinetobacter radioresistens has a Baeyer-Villiger monooxygenase (Ar-BVMO) with 100% amino acid sequence identity to the ethionamide monooxygenase of multidrug-resistant (MDR) Acinetobacter baumannii. Both enzymes are only distantly phylogenetically related to other canonical bacterial BVMO proteins. Ar-BVMO not only is capable of oxidizing two anticancer drugs metabolized by human FMO3, danusertib and tozasertib, but also can oxidize other synthetic drugs, such as imipenem. The latter is a member of the carbapenems, a clinically important antibiotic family used in the treatment of MDR bacterial infections. Susceptibility tests performed by the Kirby-Bauer disk diffusion method demonstrate that imipenem-sensitive Escherichia coli BL21 cells overexpressing Ar-BVMO become resistant to this antibiotic. An agar disk diffusion assay proved that when imipenem reacts with Ar-BVMO, it loses its antibiotic property. Moreover, an NADPH consumption assay with the purified Ar-BVMO demonstrates that this antibiotic is indeed a substrate, and its product is identified by liquid chromatography-mass spectrometry to be a Baeyer-Villiger (BV) oxidation product of the carbonyl moiety of the β-lactam ring. This is the first report of an antibiotic-inactivating BVMO enzyme that, while mediating its usual BV oxidation, also operates by an unprecedented mechanism of carbapenem resistance., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Published
2015
Full Text
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