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

Rotondo, Caitlyn M.; Marrone, Laura; Goodfellow, Valerie J.; Ghavami, Ahmad; Labbé, Geneviève; Spencer, James; Dmitrienko, Gary I.; Siemann, Stefan

doi:10.1016/j.bbagen.2015.07.012

Cited by 12 publications

(5 citation statements)

References 88 publications

(115 reference statements)

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“…The inhibitory effect was strongly substrate-dependent, suggesting the formation of a ternary complex before aggregation. Instead, the inhibitory effect on IMP-1 was moderate, confirming the relevance of the protein surface in these interactions …”

Section: Mbl Inhibitorsmentioning

confidence: 75%

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Metallo-β-lactamases in the Age of Multidrug Resistance: From Structure and Mechanism to Evolution, Dissemination, and Inhibitor Design

2021

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Antimicrobial resistance is one of the major problems in current practical medicine. The spread of genes coding for resistance determinants among bacteria challenges the use of approved antibiotics, narrowing the options for treatment. Resistance to carbapenems, last resort antibiotics, is a major concern. Metallo-β-lactamases (MBLs) hydrolyze carbapenems, penicillins, and cephalosporins, becoming central to this problem. These enzymes diverge with respect to serine-β-lactamases by exhibiting a different fold, active site, and catalytic features. Elucidating their catalytic mechanism has been a big challenge in the field that has limited the development of useful inhibitors. This review covers exhaustively the details of the active-site chemistries, the diversity of MBL alleles, the catalytic mechanism against different substrates, and how this information has helped developing inhibitors. We also discuss here different aspects critical to understand the success of MBLs in conferring resistance: the molecular determinants of their dissemination, their cell physiology, from the biogenesis to the processing involved in the transit to the periplasm, and the uptake of the Zn(II) ions upon metal starvation conditions, such as those encountered during an infection. In this regard, the chemical, biochemical and microbiological aspects provide an integrative view of the current knowledge of MBLs.

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Section: Mbl Inhibitorsmentioning

confidence: 75%

“…Instead, the inhibitory effect on IMP-1 was moderate, confirming the relevance of the protein surface in these interactions. 786 A self-assembled DNA nanoribbon was able to inhibit NDM-1, ImiS, and L1 with a nM binding affinity but unable to act against VIM-2. NDM-1 binds this nanoribbon through its minor groove.…”

Section: Allosteric Mbl Inhibitorsmentioning

confidence: 99%

Metallo-β-lactamases in the Age of Multidrug Resistance: From Structure and Mechanism to Evolution, Dissemination, and Inhibitor Design

2021

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“…Arginine-containing peptides were highly potent inhibitorsagainst VIM-2 as shown by kinetic assays in combination with fluorescence spectroscopy. The length of the arginine core and the composition of the N-terminal segment of these peptides were crucial to achieveVIM-2 inhibitors with sub-micromolaraffinity [68].…”

Section: Peptide Inhibitorsmentioning

confidence: 99%

The Development of New Small-Molecule Inhibitors Targeting Bacterial Metallo-β-lactamases

Wang

Cheng

Liu

et al. 2018

CTMC

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Metallo-β-lactamases (MBLs) are a family of Zn(II)-dependent enzymes that can hydrolyze almost all β-lactam antibiotics. Horizontal transfer of the genes encoding MBLs among Gram-negative bacteria pathogens has led to the emergence of extensively drug-resistant pathogens, which now represent a major threat to human health. As there is not to date yet a clinically available MBL inhibitor, the discovery of new MBL inhibitors has great urgency. This review highlights the recent developments in the discovery of small-molecule MBL inhibitors.

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“…La première équipe financée a travaillé sur la synthèse de la paroi cellulaire des bactéries et met en ce moment à l'essai plusieurs inhibiteurs potentiels, afin de trouver des pistes pour créer de nouveaux antibiotiques (10)(11)(12). La deuxième équipe a étudié la résistance bactérienne aux antimicrobiens de la classe des β-lactamines, ce qui a donné de nombreux résultats, y compris la conception, la synthèse et l'essai de nouveaux candidats inhibiteurs de métallo-β-lactamases, et la caractérisation de l'inhibition de cibles clés liées aux métallo-β-lactamases par des composantes connues (13,14). L'investissement dans le cadre du partenariat Canada-Royaume-Uni était de près de 4 millions de dollars et a permis aux équipes financées d'obtenir des fonds supplémentaires et de participer à d'autres partenariats, ainsi que de renforcer la capacité dans les deux domaines.…”

Section: Initiatives De Recherche Stratégique De L'imii Des Irsc Sur unclassified

Réponse des Instituts de recherche en santé du Canada à l’égard de la résistance aux antimicrobiens

Pagé¹,

S²,

Létourneau³

et al. 2015

RMTC

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La résistance aux antimicrobiens a été une priorité de recherche pour l'Institut des maladies infectieuses et immunitaires (IMII), des Instituts de recherche en santé du Canada (IRSC), depuis sa création, et de nombreuses initiatives de recherche stratégique ont été lancées pour régler ce problème de santé mondial en encourageant et en appuyant la recherche de mécanismes et de processus qui influent sur l'émergence et la propagation de la résistance chez les personnes et dans l'environnement. Nous présenterons ici des initiatives de recherche sur la résistance aux antimicrobiens menées par l'IMII des IRSC, qui comprennent des programmes nationaux ainsi que des partenariats internationaux avec le Royaume-Uni et l'Union européenne. Ces initiatives donnent d'ailleurs des résultats intéressants.

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

Cited by 12 publications

References 88 publications

Metallo-β-lactamases in the Age of Multidrug Resistance: From Structure and Mechanism to Evolution, Dissemination, and Inhibitor Design

Metallo-β-lactamases in the Age of Multidrug Resistance: From Structure and Mechanism to Evolution, Dissemination, and Inhibitor Design

The Development of New Small-Molecule Inhibitors Targeting Bacterial Metallo-β-lactamases

Réponse des Instituts de recherche en santé du Canada à l’égard de la résistance aux antimicrobiens

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