Efficacies of calcium–EDTA in combination with imipenem in a murine model of sepsis caused by Escherichia coli with NDM-1 β-lactamase

Yoshizumi, Ayumi; Ishii, Yoshikazu; Livermore, David M.; Woodford, Neil; Kimura, Soichiro; Saga, Tomoo; Harada, Sohei; Yamaguchi, Keizo; Tateda, Kazuhiro

doi:10.1007/s10156-012-0528-y

Cited by 60 publications

(61 citation statements)

References 15 publications

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“…That zinc(II) scarcity serves as a selective pressure may also help explain the success of some non-selective metal chelators to counter NDM-1 activity in animal infection models. 54–55 …”

Section: Resultsmentioning

confidence: 99%

Clinical Variants of New Delhi Metallo-β-Lactamase Are Evolving To Overcome Zinc Scarcity

Stewart¹,

Bethel

VanPelt

et al. 2017

ACS Infect. Dis.

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Use and misuse of antibiotics has driven the evolution of serine β-lactamases to better recognize new generations of β-lactam drugs, but the selective pressures driving evolution of metallo-β-lactamases are less clear. Here, we present evidence that New Delhi Metallo-β-lactamase (NDM) is evolving to overcome the selective pressure of zinc(II) scarcity. Studies of NDM-1, NDM-4 (M154L), and NDM-12 (M154L, G222D) demonstrate that the point mutant M154L, contained in 50% of clinical NDM variants, selectively enhances resistance to the penam ampicillin at low zinc(II) concentrations relevant to infection sites. Each of the clinical variants is shown to be progressively more thermostable and to bind zinc(II) more tightly than NDM-1, but a selective enhancement of penam turnover at low zinc(II) concentrations indicates that most of the improvement derives from catalysis rather than stability. X-ray crystallography of NDM-4 and NDM-12, as well as bioinorganic spectroscopy of dizinc(II), zinc(II)/cobalt(II), and dicobalt (II) metalloforms probe the mechanism of enhanced resistance and reveal perturbations of the dinuclear metal cluster that underlie improved catalysis. These studies support the proposal that zinc(II) scarcity, rather than changes in antibiotic structure, is driving the evolution of new NDM variants in clinical settings.

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Section: Resultsmentioning

confidence: 99%

Clinical Variants of New Delhi Metallo-β-Lactamase Are Evolving To Overcome Zinc Scarcity

Stewart¹,

Bethel

VanPelt

et al. 2017

ACS Infect. Dis.

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“…Furthermore, CaEDTA inhibited the activity of the elastase-type P. aeruginosa metalloprotease virulence factor. A murine neutropenic sepsis model of NDM-1-producing E. coli also showed reduced bacterial liver and blood counts after administration of imipenem-CaEDTA combinations, although the effects on overall survival were less clear (89).…”

Section: The Unique Challenge Of Class B Mbls; Closer Than We Think?mentioning

confidence: 98%

“…Two studies showed inhibitory effects of calcium-ethylenediamine-N,N,N=,N=-tetraacetic acid (CaEDTA) in whole-cell assays and murine models of MBL-producing P. aeruginosa and E. coli (Fig. 6a) (88,89). In combination with imipenem, CaEDTA improved survival and decreased bacterial burden in cases of pneumonia caused by IMP-and VIMproducing P. aeruginosa (88).…”

Section: The Unique Challenge Of Class B Mbls; Closer Than We Think?mentioning

confidence: 99%

New β-Lactamase Inhibitors: a Therapeutic Renaissance in an MDR World

Drawz

Papp-Wallace

Bonomo

2014

Antimicrob Agents Chemother

263

179

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As the incidence of Gram-negative bacterial infections for which few effective treatments remain increases, so does the contribution of drug-hydrolyzing ␤-lactamase enzymes to this serious clinical problem. This review highlights recent advances in ␤-lactamase inhibitors and focuses on agents with novel mechanisms of action against a wide range of enzymes. To this end, we review the ␤-lactamase inhibitors currently in clinical trials, select agents still in preclinical development, and older therapeutic approaches that are being revisited. Particular emphasis is placed on the activity of compounds at the forefront of the developmental pipeline, including the diazabicyclooctane inhibitors (avibactam and MK-7655) and the boronate RPX7009. With its novel reversible mechanism, avibactam stands to be the first new ␤-lactamase inhibitor brought into clinical use in the past 2 decades. Our discussion includes the importance of selecting the appropriate partner ␤-lactam and dosing regimens for these promising agents. This "renaissance" of ␤-lactamase inhibitors offers new hope in a world plagued by multidrug-resistant (MDR) Gram-negative bacteria.

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“…Accordingly, the efficacy of EDTA (Ca-EDTA) has been evaluated in a mouse model of sepsis caused by an NDM-1-producing Escherichia coli . It has been shown that a combination therapy using imipenem/cilastatin sodium (IPM/CS) and Ca-EDTA reduced the bacterial inoculum, as compared to IPM/CS alone suggesting the possibility to use Ca-EDTA in clinical therapeutics [2]. Comparison of IMP-1, VIM-2, and NDM-1 by an in silico approach revealed that NDM-1 might have greater drug profile and catalytic efficiency than IMP-1 and VIM-2 due to a larger pocket opening and a lower distance between the Zn-I ion and β -lactam oxygen of the carbapenem [3].…”

Section: Clinical Impact Of the Antibiotic Resistance Patterns Of mentioning

confidence: 99%

Worldwide Dissemination of the NDM-Type Carbapenemases in Gram-Negative Bacteria

Dortet

Poirel

Nordmann

2014

BioMed Research International

415

313

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The emergence of one of the most recently described carbapenemases, namely, the New Delhi metallo-lactamase (NDM-1), constitutes a critical and growingly important medical issue. This resistance trait compromises the efficacy of almost all lactams (except aztreonam), including the last resort carbapenems. Therapeutical options may remain limited mostly to colistin, tigecycline, and fosfomycin. The main known reservoir of NDM producers is the Indian subcontinent whereas a secondary reservoir seems to have established the Balkans regions and the Middle East. Although the spread of bla NDM-like genes (several variants) is derived mostly by conjugative plasmids in Enterobacteriaceae, this carbapenemase has also been identified in P. aeruginosa and Acinetobacter spp. Acinetobacter sp. may play a pivotal role for spreading bla NDM genes for its natural reservoir to Enterobacteriaceae. Rapid diagnostic techniques (Carba NP test) and screening of carriers are the cornerstone to try to contain this outbreak which threatens the efficacy of the modern medicine.

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Efficacies of calcium–EDTA in combination with imipenem in a murine model of sepsis caused by Escherichia coli with NDM-1 β-lactamase

Cited by 60 publications

References 15 publications

Clinical Variants of New Delhi Metallo-β-Lactamase Are Evolving To Overcome Zinc Scarcity

Clinical Variants of New Delhi Metallo-β-Lactamase Are Evolving To Overcome Zinc Scarcity

New β-Lactamase Inhibitors: a Therapeutic Renaissance in an MDR World

Worldwide Dissemination of the NDM-Type Carbapenemases in Gram-Negative Bacteria

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