Synthesis and kinetic testing of new inhibitors for a metallo-β-lactamase from Klebsiella pneumonia and Pseudomonas aeruginosa

Mohamed, Mosaad S.; Hussein, Waleed M.; McGeary, Ross P.; Vella, Peter; Schenk, Gerhard; El-Hameed, Rania Helmy Abd

doi:10.1016/j.ejmech.2011.10.030

Cited by 56 publications

(29 citation statements)

References 47 publications

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“…To illustrate, a modified form of fragment screening was employed to identify lead molecules for inhibition of the increasingly common IMP-1 enzyme, followed by in silico studies of the binding mechanisms of 1,2,4-triazole-3-thiols (85,86). While optimization of the initial thiols yielded compounds with only mid-M affinities, derivatives of thiosemicarbazides achieved low-M affinity (range of 11 to 75 M) (87).…”

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

265

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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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

265

179

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“…Mohamed et al ., [56] recently synthesized pyrrole derivatives and tested for their inhibitory activity against the IMP-1 enzyme from P. aeruginosa and Klebsiella pneumonia . They reported some compounds showing micromolar inhibition constants for IMP-1 MBL.…”

Section: Pyrrole Derivativesmentioning

confidence: 99%

An Update on the Status of Potent Inhibitors of Metallo-β-Lactamases

Faridoon

Islam²

2013

Sci. Pharm.

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The production of metallo-β-lactamases is the most important strategy by which pathogenic bacteria become resistant to currently known β-lactam antibiotics. The emergence of these enzymes is particularly concerning for the future treatment of bacterial infections. There are no clinically available drugs capable of inhibiting any of the metallo-β-lactamases, so there is an urgent need to find such inhibitors. In this review, an up-to-date status of the inhibitors investigated for the inhibition of metallo-β-lactamases has been given so that this rich source of structural information of presently known metallo-β-lactamases could be helpful in generating a broad-spectrum potent inhibitor of metallo-β-lactamases.

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“…[18][19][20][21][22][23][24] Since conventional approaches to develop MBL inhibitors have been unsuccessful so far, alternative methods are needed. One possible tactic to increase the activity of antibiotics involves their complexation with metal cations.…”

Section: Accepted Manuscriptmentioning

confidence: 99%