Use of ferrous iron by metallo-β-lactamases

Cahill, Samuel T.; Tarhonskaya, Hanna; Rydzik, Anna M.; Flashman, Emily; McDonough, M.A.; Schofield, Christopher J.; Brem, Jürgen

doi:10.1016/j.jinorgbio.2016.07.013

Cited by 21 publications

(25 citation statements)

References 77 publications

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“…As in the case of nitrocefin derivatives [ 100 ], the anionic species are quite stable, therefore, the protonation step giving rise to the product is rate-limiting [ 86 , 87 , 216 ]. The stability of the reaction intermediates is variable depending on the enzyme and substrate since it is determined by the interactions with residues near the enzyme active site [ 70 , 89 , 219 , 220 ], active site loops [ 60 , 65 ], and metal ions [ 87 , 221 ].…”

Section: Intermediate Species and Enzyme: Product Complexes As Temmentioning

confidence: 99%

Metallo-β-Lactamase Inhibitors Inspired on Snapshots from the Catalytic Mechanism

et al. 2020

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β-Lactam antibiotics are the most widely prescribed antibacterial drugs due to their low toxicity and broad spectrum. Their action is counteracted by different resistance mechanisms developed by bacteria. Among them, the most common strategy is the expression of β-lactamases, enzymes that hydrolyze the amide bond present in all β-lactam compounds. There are several inhibitors against serine-β-lactamases (SBLs). Metallo-β-lactamases (MBLs) are Zn(II)-dependent enzymes able to hydrolyze most β-lactam antibiotics, and no clinically useful inhibitors against them have yet been approved. Despite their large structural diversity, MBLs have a common catalytic mechanism with similar reaction species. Here, we describe a number of MBL inhibitors that mimic different species formed during the hydrolysis process: substrate, transition state, intermediate, or product. Recent advances in the development of boron-based and thiol-based inhibitors are discussed in the light of the mechanism of MBLs. We also discuss the use of chelators as a possible strategy, since Zn(II) ions are essential for substrate binding and catalysis.

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Section: Intermediate Species and Enzyme: Product Complexes As Temmentioning

confidence: 99%

Metallo-β-Lactamase Inhibitors Inspired on Snapshots from the Catalytic Mechanism

et al. 2020

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“…Current mechanistic models for dinuclear MBLs are exemplified by Bla2 and L1/NDM-1, respectively. [28] Upon replacement of Zn 2 + by Fe 2 + ,a ni ntermediate is observed only in BcII. The decay of this intermediate is the rate-limiting step in the reaction.…”

Section: Aim-1 Is Inhibited By Its Substrates and Displays Substratedmentioning

confidence: 99%

AIM‐1: An Antibiotic‐Degrading Metallohydrolase That Displays Mechanistic Flexibility

Selleck

Larrabee

Harmer

et al. 2016

Chemistry A European J

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Antibiotic resistance has emerged as a major threat to global health care. This is largely due to the fact that many pathogens have developed strategies to acquire resistance to antibiotics. Metallo-β-lactamases (MBL) have evolved to inactivate most of the commonly used β-lactam antibiotics. AIM-1 is one of only a few MBLs from the B3 subgroup that is encoded on a mobile genetic element in a major human pathogen. Here, its mechanism of action was characterised with a combination of spectroscopic and kinetic techniques and compared to that of other MBLs. Unlike other MBLs it appears that AIM-1 has two avenues available for the turnover of the substrate nitrocefin, distinguished by the identity of the rate-limiting step. This observation may be relevant with respect to inhibitor design for this group of enzymes as it demonstrates that at least some MBLs are very flexible in terms of interactions with substrates and possibly inhibitors.

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“…31 This metalloenzyme may have some advantages when competing for metal ion binding because its periplasmic location could facilitate access to extracellular zinc and because some metallo-β-lactamases can substitute alternative divalent metal ions if zinc(II) is not available. 31–34 The Zn1 of NDM-1 is bound tightly, and the Zn2 site has a K d value estimated, by changes in activity, to be in the low micromolar range (2 μM). 35 The concentration of zinc(II) at typical infection sites appears to be in a similar range.…”

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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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Use of ferrous iron by metallo-β-lactamases

Cited by 21 publications

References 77 publications

Metallo-β-Lactamase Inhibitors Inspired on Snapshots from the Catalytic Mechanism

Metallo-β-Lactamase Inhibitors Inspired on Snapshots from the Catalytic Mechanism

AIM‐1: An Antibiotic‐Degrading Metallohydrolase That Displays Mechanistic Flexibility

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

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