B1-Metallo-β-Lactamases: Where Do We Stand?

Mojica, María F; Bonomo, Robert A.; Fast, Walter

doi:10.2174/1389450116666151001105622

Cited by 183 publications

(175 citation statements)

References 168 publications

(260 reference statements)

Supporting

Mentioning

173

Contrasting

Unclassified

Order By: Relevance

“…Pairwise protein sequence alignments between all combinations of the three MBLs tested here (NDM-1, IMP-1, and VIM-2) have identities of approximately only 30%. 9,25 This diversity is also present at the active site where very few residues are essential for catalysis due to a mechanism that relies mostly on substrate interactions with the di-Zn(II) site. 9 However, this same property makes the di-Zn(II) active site an attractive target for inhibition by MBPs.…”

Section: Resultsmentioning

confidence: 99%

Dipicolinic Acid Derivatives as Inhibitors of New Delhi Metallo-β-lactamase-1

et al. 2017

Self Cite

View full text Add to dashboard Cite

The efficacy of β-lactam antibiotics is threatened by the emergence and global spread of metallo-β-lactamase-(MBL) mediated resistance, specifically New Delhi-Metallo-β-lactamase-1 (NDM-1). Utilizing fragment-based drug discovery (FBDD), a new class of inhibitors for NDM-1 and two related β-lactamases, IMP-1 and VIM-2, was identified. Based on 2,6-dipicolinic acid (DPA), several libraries were synthesized for structure-activity relationship (SAR) analysis. Inhibitor 36 (IC50 = 80 nM) was identified to be highly selective for MBLs when compared to other Zn(II) metalloenzymes. While DPA displayed a propensity to chelate metal ions from NDM-1, 36 formed a stable NDM-1:Zn(II):inhibitor ternary complex, as demonstrated by 1H NMR, electron paramagnetic resonance (EPR) spectroscopy, equilibrium dialysis, intrinsic tryptophan fluorescence emission, and UV-Vis spectroscopy. When co-administered with 36 (at concentrations non-toxic to mammalian cells), the minimum inhibitory concentration (MIC) of imipenem against clinical isolates of Eschericia coli and Klebsiella pneumoniae harboring NDM-1 were reduced to susceptible levels.

show abstract

Section: Resultsmentioning

confidence: 99%

Dipicolinic Acid Derivatives as Inhibitors of New Delhi Metallo-β-lactamase-1

et al. 2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…MBLs possess a shallow active-site groove with one or two divalent zinc ions, bordered by flexible loops [8]. In NDM-1 this flexible hairpin loop moves over the zinc ion for hydrolysis and is later removed after the catalysis [9].…”

Section: Introductionmentioning

confidence: 99%

“…MBLs are classified into three subclasses (B1, B2 and B3), according to sequence identity and zinc ion dependence, of which the B1 subclass included most clinically significant enzymes. Not many inhibitors have been successfully designed due to the nature of zinc ligands, catalytic mechanisms and the differences among the active site architecture [8]. The evolution of varied and detrimental range of β-lactamases has lost the effectiveness of β-Lactamase inhibitors (BLIs) which could play an important role in combating β-lactam resistance in Gram-negative bacteria [10].…”

Section: Introductionmentioning

confidence: 99%

Structure, Genetics and Worldwide Spread of New Delhi Metallo-β-lactamase (NDM): a threat to public health

Khan

Maryam

Zarrilli³

2017

BMC Microbiol

427

295

View full text Add to dashboard Cite

BackgroundThe emergence of carbapenemase producing bacteria, especially New Delhi metallo-β-lactamase (NDM-1) and its variants, worldwide, has raised amajor public health concern. NDM-1 hydrolyzes a wide range of β-lactam antibiotics, including carbapenems, which are the last resort of antibiotics for the treatment of infections caused by resistant strain of bacteria.Main bodyIn this review, we have discussed bla NDM-1variants, its genetic analysis including type of specific mutation, origin of country and spread among several type of bacterial species. Wide members of enterobacteriaceae, most commonly Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, and gram-negative non-fermenters Pseudomonas spp. and Acinetobacter baumannii were found to carry these markers. Moreover, at least seventeen variants of bla NDM-type gene differing into one or two residues of amino acids at distinct positions have been reported so far among different species of bacteria from different countries. The genetic and structural studies of these variants are important to understand the mechanism of antibiotic hydrolysis as well as to design new molecules with inhibitory activity against antibiotics.ConclusionThis review provides a comprehensive view of structural differences among NDM-1 variants, which are a driving force behind their spread across the globe.Electronic supplementary materialThe online version of this article (doi:10.1186/s12866-017-1012-8) contains supplementary material, which is available to authorized users.

show abstract

“…20–21 However, NDM is already a highly efficient catalyst with broad substrate selectivity that encompasses all of the clinically-used classes of β-lactams, excepting monobactams. 18, 22 A need to alter substrate selectivity may not be a significant selective pressure placed on NDM-encoding microorganisms. In support of this idea, it is notable that most of the identified NDM variants confer only limited changes in catalytic activity and substrate selectivity.…”

mentioning

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.

Self Cite

View full text Add to dashboard Cite

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.

show abstract

B1-Metallo-β-Lactamases: Where Do We Stand?

Cited by 183 publications

References 168 publications

Dipicolinic Acid Derivatives as Inhibitors of New Delhi Metallo-β-lactamase-1

Dipicolinic Acid Derivatives as Inhibitors of New Delhi Metallo-β-lactamase-1

Structure, Genetics and Worldwide Spread of New Delhi Metallo-β-lactamase (NDM): a threat to public health

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

Contact Info

Product

Resources

About