Ebselen as a potent covalent inhibitor of New Delhi metallo-β-lactamase (NDM-1)

Chiou, Jiachi; Wan, Shengbiao; Chan, Kin‐Fai; So, Pui‐Kin; He, Dongjian; Chan, Edward Wai-Chi; Chan, T.C.L.; Wong, Kwok Yin; Jiang, Tao; Chen, Sheng

doi:10.1039/c5cc02594j

Cited by 120 publications

(83 citation statements)

References 38 publications

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“…Representative inhibitors of NDM-1 [28][29][30][31][32][33][34][35][36]. ChemMedChem 2019, 14,1271 -1282 www.chemmedchem.org 2019 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim 3, 5, 6,a nd 8 are summarized in Scheme 2.…”

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confidence: 99%

Investigation of Dipicolinic Acid Isosteres for the Inhibition of Metallo‐β‐Lactamases

et al. 2019

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New Delhi metallo‐β‐lactamase‐1 (NDM‐1) poses an immediate threat to our most effective and widely prescribed drugs, the β‐lactam‐containing class of antibiotics. There are no clinically relevant inhibitors to combat NDM‐1, despite significant efforts toward their development. Inhibitors that use a carboxylic acid motif for binding the ZnII ions in the active site of NDM‐1 make up a large portion of the >500 inhibitors reported to date. New and structurally diverse scaffolds for inhibitor development are needed urgently. Herein we report the isosteric replacement of one carboxylate group of dipicolinic acid (DPA) to obtain DPA isosteres with good inhibitory activity against NDM‐1 (and related metallo‐β‐lactamases, IMP‐1 and VIM‐2). It was determined that the choice of carboxylate isostere influences both the potency of NDM‐1 inhibition and the mechanism of action. Additionally, we show that an isostere with a metal‐stripping mechanism can be re‐engineered into an inhibitor that favors ternary complex formation. This work provides a roadmap for future isosteric replacement of routinely used metal binding motifs (i.e., carboxylic acids) for the generation of new entities in NDM‐1 inhibitor design and development.

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confidence: 99%

Investigation of Dipicolinic Acid Isosteres for the Inhibition of Metallo‐β‐Lactamases

et al. 2019

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“…The notion of the involvement of interactions other than electrostatic derives further support from the observation that the replacement of arginine by lysine residues resulted in the abolishment of the peptides' inhibitory potency. which has been shown to not only inactivate NDM-1 and VIM-2, but also reverse carbapenem resistance in vivo [81]; (iv) ebselen, a seleno compound which targets Cys221 in NDM-1 resulting in the loss of one of its zinc ions [82]; and (v) clinically already approved thiolcontaining drugs which have been found to inhibit NDM-1, VIM-1 and IMP-7 in the low micromolar range [83]. The arginine-containing peptides described in the current report add to this list because they not only serve as very potent (nanomolar) inhibitors of VIM-2 (and potentially other MBLs), but also appear to be unique in that they trigger aggregation of the enzyme (at least at the concentrations employed for the spectroscopic investigations).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Arginine-containing peptides as potent inhibitors of VIM-2 metallo-β-lactamase

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Goodfellow

et al. 2015

Biochimica et Biophysica Acta (BBA) - General Subjects

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“…It is worth mentioning that Chiou proposed a selenium‐containing inhibition called ebselen (Figure .20), which has been shown to effectively inactivate NDM‐1 and restore meropenem activity on NDM‐1. Electrospray ionization mass spectrometry (ESI‐MS) analysis indicated that it can bind to NDM‐1 by forming an S‐Se bond at the active site with the Cys221 residue (Chiou et al., ).…”

Section: Progress In Designing Metallo‐β‐lactamase Inhibitorsmentioning

confidence: 99%

Approaches for the discovery of metallo‐β‐lactamase inhibitors: A review

et al. 2019

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After more than 80 years of development, β‐lactam drugs have become the most widely used high‐efficiency, low‐toxic broad‐spectrum antibacterial drugs. However, with the widespread use and even abuse of those drugs, the resistance of major pathogens to β‐lactam drugs has increased over years, which has become a thorny problem to the public health. A common mechanism of the resistance to β‐lactams is the producing of β‐lactamases, which can hydrolyze the β‐lactam ring and inactivate these drugs. Metallo‐β‐lactamases (MBLs) are one kind of β‐lactamases that require metal ions for their catalytic activities. Although it is a well‐known strategy to recover the efficacy of β‐lactams by the combination of β‐lactamase inhibitors, there are still no MBL inhibitors that can be used in clinical practice. Therefore, it is urgent to develop MBL inhibitors. This review outlines the currently discovered MBL inhibitors with an emphasis on various strategies and approaches taken to discover MBL inhibitors, which may lead to diverse classes of inhibitors. Recent progress, particularly new screening methods, and the rational design of potent MBL inhibitors are discussed.

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Ebselen as a potent covalent inhibitor of New Delhi metallo-β-lactamase (NDM-1)

Cited by 120 publications

References 38 publications

Investigation of Dipicolinic Acid Isosteres for the Inhibition of Metallo‐β‐Lactamases

Investigation of Dipicolinic Acid Isosteres for the Inhibition of Metallo‐β‐Lactamases

Arginine-containing peptides as potent inhibitors of VIM-2 metallo-β-lactamase

Approaches for the discovery of metallo‐β‐lactamase inhibitors: A review

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