Structural Basis of Metallo-β-lactamase Inhibition by<i>N</i>-Sulfamoylpyrrole-2-carboxylates

Farley, Alistair J. M.; Ermolovich, Yurii V.; Calvopiña, Karina; Rabe, Patrick; Panduwawala, Tharindi; Brem, Jürgen; Björkling, Fredrik; Schofield, Christopher J.

doi:10.1021/acsinfecdis.1c00104

Cited by 22 publications

(12 citation statements)

References 46 publications

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“…The β-lactam ring is covalently bound to the active serine (Ser307) present in PBP3. ,, It thus interrupts the peptidoglycan monomer cross-linking process and prevents bacteria from synthesizing intact cell walls. Molecular simulations reveal that GOβL can block the channel in front of the active serine binding site and inhibit the entry of peptidoglycan monomers into the active serine site. , It acts as a peptide chain blocker, leading to the inability to produce an intact cell wall because of the large GO layer in GOβL. In this study, the Gram-positive bacteria (S.…”

Section: Resultsmentioning

confidence: 88%

Fast Synthesis of Graphene Oxide−β-Lactam as a Residue-Free Environmental Bacterial Inhibitor

Heng

Zeng

et al. 2022

ACS Omega

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Common pathogenic bacteria contaminate the environment through various modes of transmission. It is thus crucial to develop simple preparation methods of residue-free environmental disinfectants. β-Lactam antibiotics are frequently prescribed in clinical practice to treat bacterial infections. In this study, we used electrochemical exfoliation to synthesize graphene oxide (GO) with abundant ketene functional groups. A residue-free GO−β-lactam (GOβL) was subsequently obtained by mixing ketene and azomethine-H via a [2 + 2] cycloaddition reaction in the aqueous phase. GOβL has shown broad-spectrum bacterial inhibition against four bacteria ( Staphylococcus aureus , Escherichia coli , Salmonella enterica , and Shigella dysenteriae ), and it degrades rapidly within 24 h. This study provides a fast and easy method for the synthesis of GOβL, which can be employed as a promising environmental bacteriostatic disinfectant in real-life applications.

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Section: Resultsmentioning

confidence: 88%

Fast Synthesis of Graphene Oxide−β-Lactam as a Residue-Free Environmental Bacterial Inhibitor

Heng

Zeng

et al. 2022

ACS Omega

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“…All of the selected compounds show inhibition of NDM-1, and fits indicate a range of estimated IC 50 values between 0.045 and >10 μM. A known NDM-1 inhibitor (2,6-dipicolinic acid) is found among these hits, as are other compounds with pharmacophores shown earlier to either inhibit MBLs or to bind metal ions: 8-hydroxyquinolines (6 compounds), sulfates or sulfonamides , (10 compounds), thiols (4 compounds), and compounds with potential zinc-bridging sulfur atoms (39 compounds). The rediscovery of these MBL inhibitor motifs provides evidence that our HTS workflow can successfully identify NDM-1 inhibitors.…”

Section: Resultsmentioning

confidence: 96%

Discovery of an Effective Small-Molecule Allosteric Inhibitor of New Delhi Metallo-β-lactamase (NDM)

et al. 2022

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To identify novel inhibitors of the carbapenemase New Delhi metallo-β-lactamase (NDM) as possible therapeutic compounds, we conducted a high-throughput screen of a 43,358compound library. One of these compounds, a 2-quinazolinone linked through a diacylhydrazine to a phenyl ring (QDP-1) (IC 50 = 7.9 ± 0.5 μM), was characterized as a slow-binding reversible inhibitor (K i app = 4 ± 2 μM) with a noncompetitive mode of inhibition in which substrate and inhibitor enhance each other's binding affinity. These studies, along with differential scanning fluorimetry, zinc quantitation, and selectivity studies, support an allosteric mechanism of inhibition. Cotreatment with QDP-1 effectively lowers minimum inhibitory concentrations of carbapenems for a panel of resistant Escherichia coli and Klebsiella pneumoniae clinical isolates expressing NDM-1 but not for those expressing only serine carbapenemases. QDP-1 represents a novel allosteric approach for NDM drug development for potential use alone or with other NDM inhibitors to counter carbapenem resistance in enterobacterales.

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“…The spatial position of the Asn233 side chain shifted toward the zinc ions. One carboxylate oxygen coordinates with Zn2, while the other one interacts with the amide of Asn233 and the amino group of either Lys224 (IMP-1, NDM-1) or Arg228 (VIM-2) [123,147].…”

Section: Binding Modes Of Blismentioning

confidence: 99%

Recent Developments to Cope the Antibacterial Resistance via β-Lactamase Inhibition

et al. 2022

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Antibacterial resistance towards the β-lactam (BL) drugs is now ubiquitous, and there is a major global health concern associated with the emergence of new β-lactamases (BLAs) as the primary cause of resistance. In addition to the development of new antibacterial drugs, β-lactamase inhibition is an alternative modality that can be implemented to tackle this resistance channel. This strategy has successfully revitalized the efficacy of a number of otherwise obsolete BLs since the discovery of the first β-lactamase inhibitor (BLI), clavulanic acid. Over the years, β-lactamase inhibition research has grown, leading to the introduction of new synthetic inhibitors, and a few are currently in clinical trials. Of note, the 1, 6-diazabicyclo [3,2,1]octan-7-one (DBO) scaffold gained the attention of researchers around the world, which finally culminated in the approval of two BLIs, avibactam and relebactam, which can successfully inhibit Ambler class A, C, and D β-lactamases. Boronic acids have shown promise in coping with Ambler class B β-lactamases in recent research, in addition to classes A, C, and D with the clinical use of vaborbactam. This review focuses on the further developments in the synthetic strategies using DBO as well as boronic acid derivatives. In addition, various other potential serine- and metallo- β-lactamases inhibitors that have been developed in last few years are discussed briefly as well. Furthermore, binding interactions of the representative inhibitors have been discussed based on the crystal structure data of inhibitor-enzyme complex, published in the literature.

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Structural Basis of Metallo-β-lactamase Inhibition byN-Sulfamoylpyrrole-2-carboxylates

Cited by 22 publications

References 46 publications

Fast Synthesis of Graphene Oxide−β-Lactam as a Residue-Free Environmental Bacterial Inhibitor

Fast Synthesis of Graphene Oxide−β-Lactam as a Residue-Free Environmental Bacterial Inhibitor

Discovery of an Effective Small-Molecule Allosteric Inhibitor of New Delhi Metallo-β-lactamase (NDM)

Recent Developments to Cope the Antibacterial Resistance via β-Lactamase Inhibition

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