An Elusive Task: A Clinically Useful Inhibitor of Metallo-β-Lactamases

González, Mariano M.; Vila, Alejandro J.

doi:10.1007/7355_2016_6

Cited by 8 publications

(8 citation statements)

References 135 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Utilization of metal-binding inhibitors to overcome MBL-mediated resistance is unsurprising as the active site metal center of MBLs is their defining feature and constitutes the most conserved region of this diverse family of enzymes [12]. Metal binding inhibitors function within two limiting mechanisms: 1) metal ion stripping, where the inhibitor either actively removes the active-site metal ions from the enzyme or sequesters metal ions that exited the active site; or 2) ternary complex formation, where the inhibitor binds to the metal ions and the surrounding protein residues, preventing antibiotics from binding.…”

Section: Mechanism Of Metal Ion Bindingmentioning

confidence: 99%

“…Previous studies have indicated that conserved, non-metal features of MBLs ( e.g. , a substrate-binding β-hairpin loop in B1 MBLs or a neighboring α-helix in B2 MBLs) can play a role in binding and catalysis [12, 54]. It is likely these features interact with inhibitors to increase binding affinity [12].…”

Section: Spectroscopic Studies On Mbl-inhibitor Complexesmentioning

confidence: 99%

See 1 more Smart Citation

The Continuing Challenge of Metallo-β-Lactamase Inhibition: Mechanism Matters

Ju¹,

Cheng²,

Fast³

et al. 2018

Trends in Pharmacological Sciences

121

116

View full text Add to dashboard Cite

Metallo-β-lactamases (MBLs) are a significant clinical problem because they hydrolyze and inactivate nearly all β-lactam-containing antibiotics. These 'lifesaving drugs' constitute >50% of the available contemporary antibiotic arsenal. Despite the global spread of MBLs, MBL inhibitors have not yet appeared in clinical trials. Most MBL inhibitors target active site zinc ions and vary in mechanism from ternary complex formation to metal ion stripping. Importantly, differences in mechanism can impact pharmacology in terms of reversibility, target selectivity, and structure-activity relationship interpretation. This review surveys the mechanisms of MBL inhibitors and describes methods that determine the mechanism of inhibition to guide development of future therapeutics.

show abstract

Section: Mechanism Of Metal Ion Bindingmentioning

confidence: 99%

Section: Spectroscopic Studies On Mbl-inhibitor Complexesmentioning

confidence: 99%

The Continuing Challenge of Metallo-β-Lactamase Inhibition: Mechanism Matters

Ju¹,

Cheng²,

Fast³

et al. 2018

Trends in Pharmacological Sciences

121

116

View full text Add to dashboard Cite

show abstract

“…The enzyme kinetics can then be investigated by constructing a high‐throughput inhibitor screening model to find inhibitors of metalloenzymes. New screening methods have been developed recently, which not only improve the screening efficiency of different types of inhibitors, but also help researchers design more novel MBL inhibitors (González & Alejandro, ).…”

Section: Discovery and Screening Approaches For Mbl Inhibitorsmentioning

confidence: 99%

Approaches for the discovery of metallo‐β‐lactamase inhibitors: A review

et al. 2019

View full text Add to dashboard Cite

After more than 80 years of development, β‐lactam drugs have become the most widely used high‐efficiency, low‐toxic broad‐spectrum antibacterial drugs. However, with the widespread use and even abuse of those drugs, the resistance of major pathogens to β‐lactam drugs has increased over years, which has become a thorny problem to the public health. A common mechanism of the resistance to β‐lactams is the producing of β‐lactamases, which can hydrolyze the β‐lactam ring and inactivate these drugs. Metallo‐β‐lactamases (MBLs) are one kind of β‐lactamases that require metal ions for their catalytic activities. Although it is a well‐known strategy to recover the efficacy of β‐lactams by the combination of β‐lactamase inhibitors, there are still no MBL inhibitors that can be used in clinical practice. Therefore, it is urgent to develop MBL inhibitors. This review outlines the currently discovered MBL inhibitors with an emphasis on various strategies and approaches taken to discover MBL inhibitors, which may lead to diverse classes of inhibitors. Recent progress, particularly new screening methods, and the rational design of potent MBL inhibitors are discussed.

show abstract

“…Despite the low success rates, over 900 inhibitors have been reported in literature as of October 2019. Given this number of compounds, there have been several review articles that have categorized the inhibitors based on structure [33,34] or mechanism of inhibition [12,17]. While these articles provide excellent insights to existing MBL inhibitors, and often suggest future directions, most review articles focus on the best inhibitors and do not often discuss compounds with relatively poor inhibition properties, even though these latter compounds may be great scaffolds for redesign efforts.…”

Section: Introductionmentioning

confidence: 99%

MBLinhibitors.com, a Website Resource Offering Information and Expertise for the Continued Development of Metallo-β-Lactamase Inhibitors

et al. 2020

View full text Add to dashboard Cite

In an effort to facilitate the discovery of new, improved inhibitors of the metallo-β-lactamases (MBLs), a new, interactive website called MBLinhibitors.com was developed. Despite considerable efforts from the science community, there are no clinical inhibitors of the MBLs, which are now produced by human pathogens. The website, MBLinhibitors.com, contains a searchable database of known MBL inhibitors, and inhibitors can be searched by chemical name, chemical formula, chemical structure, Simplified Molecular-Input Line-Entry System (SMILES) format, and by the MBL on which studies were conducted. The site will also highlight a "MBL Inhibitor of the Month", and researchers are invited to submit compounds for this feature. Importantly, MBLinhibitors.com was designed to encourage collaboration, and researchers are invited to submit their new compounds, using the "Submit" function on the site, as well as their expertise using the "Collaboration" function. The intention is for this site to be interactive, and the site will be improved in the future as researchers use the site and suggest improvements. It is hoped that MBLinhibitors.com will serve as the one-stop site for any important information on MBL inhibitors and will aid in the discovery of a clinically useful MBL inhibitor.

show abstract

An Elusive Task: A Clinically Useful Inhibitor of Metallo-β-Lactamases

Cited by 8 publications

References 135 publications

The Continuing Challenge of Metallo-β-Lactamase Inhibition: Mechanism Matters

The Continuing Challenge of Metallo-β-Lactamase Inhibition: Mechanism Matters

Approaches for the discovery of metallo‐β‐lactamase inhibitors: A review

MBLinhibitors.com, a Website Resource Offering Information and Expertise for the Continued Development of Metallo-β-Lactamase Inhibitors

Contact Info

Product

Resources

About