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

Abstract：

: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.

journal_name

ACS Infect Dis

journal_title

ACS infectious diseases

authors

Linciano P,Cendron L,Gianquinto E,Spyrakis F,Tondi D

doi

10.1021/acsinfecdis.8b00247

subject

Has Abstract

pub_date

2019-01-11 00:00:00

pages

9-34

issue

1

issn

2373-8227

journal_volume

5

pub_type

杂志文章,评审

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