<i>In Silico</i> Identification and Experimental Validation of Novel KPC-2 β-lactamase Inhibitors

Klein, Raphael; Linciano, Pasquale; Celenza, Giuseppe; Bellio, Pierangelo; Papaioannou, S.; Blázquez, Jesús; Cendron, Laura; Brenk, Ruth; Tondi, Donatella

doi:10.1101/396283

Cited by 1 publication

(1 citation statement)

References 41 publications

(41 reference statements)

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“…While for SBLs several mechanism-based inhibitors are available in therapy and extensive structure-based drug design efforts continue to be effective, − a specific and efficacious inhibitor against NDM-1 is still missing in clinic. The lack of effective MBL inhibitors could be mainly attributed to the structural diversity of the active sites among the three different MBL classes, to the variability of the loop arrangement at the active site entrance, and to the presence of several NDM-1 variants.…”

Section: Ndm-1 Inhibitorsmentioning

confidence: 99%

Ten Years with New Delhi Metallo-β-lactamase-1 (NDM-1): From Structural Insights to Inhibitor Design

et al. 2018

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The worldwide emergence of New Delhi metallo-β-lactamase-1 (NDM-1) as a carbapenemase able to hydrolyze nearly all available β-lactam antibiotics has characterized the past decade, endangering efficacious antibacterial treatments. No inhibitors for NDM-1 are available in therapy, nor are promising compounds in the pipeline for future NDM-1 inhibitors. We report the studies dedicated to the design and development of effective NDM-1 inhibitors. The discussion for each agent moves from the employed design strategy to the ability of the identified inhibitor to synergize β-lactam antibiotics. A structural analysis of NDM-1 mechanism of action based on selected X-ray complexes is also reported: the intrinsic flexibility of the binding site and the comparison between penicillin/cephalosporin and carbapenem mechanisms of hydrolysis are evaluated. Despite the valuable progress in terms of structural and mechanistic information, the design of a potent NDM-1 inhibitor to be introduced in therapy remains challenging. Certainly, only the deep knowledge of NDM-1 architecture and of the variable mechanism of action that NDM-1 employs against different classes of substrates could orient a successful drug discovery campaign.

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