Journal ArticleDOI
Challenges in the Development of a Thiol-Based Broad-Spectrum Inhibitor for Metallo-β-Lactamases
Dominik Büttner,Jan S. Kramer,Franca Maria Klingler,Sandra K. Wittmann,Markus Hartmann,Christian Kurz,Daniel Kohnhäuser,Lilia Weizel,Astrid Brüggerhoff,Denia Frank,Dieter Steinhilber,Thomas A. Wichelhaus,Denys Pogoryelov,Ewgenij Proschak +13 more
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TLDR
The synthesis and biochemical characterization of thiol-based MBL inhibitors are reported and the challenges behind the development are highlighted, which exhibit good in vitro activity toward a broad spectrum of MBLs, selectivity against human off-targets, and reasonable activity against clinical isolates.Abstract:
Pathogens, expressing metallo-β-lactamases (MBLs), become resistant against most β-lactam antibiotics. Besides the dragging search for new antibiotics, development of MBL inhibitors would be an alternative weapon against resistant bacterial pathogens. Inhibition of resistance enzymes could restore the antibacterial activity of β-lactams. Various approaches to MBL inhibitors are described; among others, the promising motif of a zinc coordinating thiol moiety is very popular. Nevertheless, since the first report of a thiol-based MBL inhibitor (thiomandelic acid) in 2001, no steps in development of thiol based MBL inhibitors were reported that go beyond clinical isolate testing. In this study, we report on the synthesis and biochemical characterization of thiol-based MBL inhibitors and highlight the challenges behind the development of thiol-based compounds, which exhibit good in vitro activity toward a broad spectrum of MBLs, selectivity against human off-targets, and reasonable activity against clinical is...read more
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Journal ArticleDOI
Metallo-β-Lactamases: Structure, Function, Epidemiology, Treatment Options, and the Development Pipeline.
TL;DR: Owing to their unique structure and function and their diversity, MBLs pose a particular challenge for drug development, although several stable agents and inhibitor combinations are at various stages in the development pipeline.
Journal ArticleDOI
The Continuing Challenge of Metallo-β-Lactamase Inhibition: Mechanism Matters
TL;DR: This review surveys the mechanisms of MBL inhibitors and describes methods that determine the mechanism of inhibition to guide development of future therapeutics.
Journal ArticleDOI
Ten Years with New Delhi Metallo-β-lactamase-1 (NDM-1): From Structural Insights to Inhibitor Design.
TL;DR: The studies dedicated to the design and development of effective NDM-1 inhibitors are reported: the discussion for each agent moves from the employed design strategy to the ability of the identified inhibitor to synergize β-lactam antibiotics.
Journal ArticleDOI
β-lactam/β-lactamase inhibitor combinations : an update
TL;DR: An overview of recent FDA-approved β- lactam/β-lactamase inhibitor combinations as well as an update on research efforts aimed at the discovery and development of novel β-lacticamase inhibitors are provided.
Journal ArticleDOI
Metallo-β-lactamases in the Age of Multidrug Resistance: From Structure and Mechanism to Evolution, Dissemination, and Inhibitor Design.
TL;DR: In this article, a review of the active site and catalytic mechanism of Metallo-β-lactamases (MBLs) is presented, and the success of MBLs in conferring resistance to carbapenems, penicillins, and cephalosporins.
References
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Journal ArticleDOI
Trends and exceptions of physical properties on antibacterial activity for Gram-positive and Gram-negative pathogens.
TL;DR: Physical properties of antibacterial project compounds with whole cell activity against Gram-negative or Gram-positive pathogens were profiled and compared to actives found from high throughput screens conducted on both biochemical and phenotypic bacterial targets and illustrated that compounds least susceptible to efflux were those which were highly polar and small in MW or very large and typically zwitterionic.
Journal ArticleDOI
Revised Ambler classification of β-lactamases
Barry G. Hall,Miriam Barlow +1 more
TL;DR: The current nomenclature presents two immediate problems: the actual amount of diversity that exists among the metallob-lactamases is under-represented and is therefore scientifically misleading; and it is implied that all subgroupings of the class B enzymes are equal, and this is not the case.
Journal ArticleDOI
The Challenge of Overcoming Antibiotic Resistance: An Adjuvant Approach?
TL;DR: Some of the advantages and disadvantages of the use of adjuvants, and various approaches to their identification are described, which have the potential to render an antibiotic against which bacteria have developed resistance once again effective.
Journal ArticleDOI
A structural view of the antibiotic degradation enzyme NDM-1 from a superbug
Yu Guo,Jing Wang,Niu Guojun,Wenqing Shui,Yuna Sun,Honggang Zhou,Yaozhou Zhang,Cheng Yang,Zhiyong Lou,Zihe Rao +9 more
TL;DR: Biological and mass spectroscopy results revealed that D-captopril can effectively inhibit the enzymatic activity of NDM-1 by binding to its active site with high binding affinity, and unique features concerning the primary sequence and structural conformation of the active site distinguish N DM-1 from other reported metallo-β-lactamases and implicate its role in wide spectrum drug resistance.
Journal ArticleDOI
New β-Lactamase Inhibitors in the Clinic
TL;DR: Two β-lactam-β- lactamase inhibitor (BL-BLI) combinations, ceftolozane-tazobactam and ceftazidime-avibactam, that recently entered the clinic are reviewed.