In Silico Fragment-Based Design Identifies Subfamily B1 Metallo-β-lactamase Inhibitors

Cain, Ricky; Brem, Jürgen; Zollman, David; McDonough, M.A.; Johnson, Rachel M.; Spencer, James; Makena, Anne; Abboud, Martine I.; Cahill, Samuel T.; Lee, Sook Y.; McHugh, Peter J.; Schofield, Christopher J.; Fishwick, Colin W. G.

doi:10.1021/acs.jmedchem.7b01728

Cited by 45 publications

(26 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Representative inhibitors of NDM-1 [28][29][30][31][32][33][34][35][36]. ChemMedChem 2019, 14,1271 -1282 www.chemmedchem.org 2019 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim 3, 5, 6,a nd 8 are summarized in Scheme 2.…”

mentioning

confidence: 99%

Investigation of Dipicolinic Acid Isosteres for the Inhibition of Metallo‐β‐Lactamases

et al. 2019

View full text Add to dashboard Cite

New Delhi metallo‐β‐lactamase‐1 (NDM‐1) poses an immediate threat to our most effective and widely prescribed drugs, the β‐lactam‐containing class of antibiotics. There are no clinically relevant inhibitors to combat NDM‐1, despite significant efforts toward their development. Inhibitors that use a carboxylic acid motif for binding the ZnII ions in the active site of NDM‐1 make up a large portion of the >500 inhibitors reported to date. New and structurally diverse scaffolds for inhibitor development are needed urgently. Herein we report the isosteric replacement of one carboxylate group of dipicolinic acid (DPA) to obtain DPA isosteres with good inhibitory activity against NDM‐1 (and related metallo‐β‐lactamases, IMP‐1 and VIM‐2). It was determined that the choice of carboxylate isostere influences both the potency of NDM‐1 inhibition and the mechanism of action. Additionally, we show that an isostere with a metal‐stripping mechanism can be re‐engineered into an inhibitor that favors ternary complex formation. This work provides a roadmap for future isosteric replacement of routinely used metal binding motifs (i.e., carboxylic acids) for the generation of new entities in NDM‐1 inhibitor design and development.

show abstract

mentioning

confidence: 99%

Investigation of Dipicolinic Acid Isosteres for the Inhibition of Metallo‐β‐Lactamases

et al. 2019

View full text Add to dashboard Cite

show abstract

“…135 Other studies employed mercaptoacetamide thioethers containing acetate 136 and azolyl ring [137][138][139][140] substituents. The diverse library of thiolcontaining MBL-inhibitors also include thiomethylbenzoic acids, 141 bisthiazolidines, 142,143 rhodanines and its related thioenolates, [144][145][146][147] cysteine-containing oligopeptides, 148,149 phosphonate and tetrazole bioisosters of mercaptoacids 150 and thiones. [151][152][153][154] Finally, it should be added that although thiols are among the most potent and broad-spectrum inhibitors of MBLs, their tendency to rapidly oxidize to disulfides poses a serious challenge to further clinical developments.…”

Section: Recent Advances In the Development Of Mbl Inhibitorsmentioning

confidence: 99%

β-lactam/β-lactamase inhibitor combinations: an update

2018

View full text Add to dashboard Cite

show abstract

“…However, these inhibitors display low inhibitory activity against other members of VIM or other B1 enzymes. In the next study, Schofield group identified several thiol MBL inhibitors based on the design of silico fragment, which has significant inhibitory effects on NDM‐1, VIM‐2, and IMP‐1 (Cain et al., ). Interestingly, the crystal structure of compound 1 (Figure .22) and VIM‐1 showed that it acts as a metal‐binding ligand, replacing the “hydrolyzed” hydroxide ion bridging the two metal ions.…”

Section: Progress In Designing Metallo‐β‐lactamase Inhibitorsmentioning

confidence: 99%

“…Cain report an application of silico fragment‐based molecular design employing thiol‐mediated metal anchorage leads to potent MBL inhibitors. The new inhibitors are effective in inhibiting the important B1 subfamily MBLs (NDM‐1, IMP‐1, and VIM‐2), while some of them also have a lower inhibitory effect on clinically relevant class A and class D serine‐β‐lactamase (Cain et al., ).…”

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

In Silico Fragment-Based Design Identifies Subfamily B1 Metallo-β-lactamase Inhibitors

Cited by 45 publications

References 32 publications

Investigation of Dipicolinic Acid Isosteres for the Inhibition of Metallo‐β‐Lactamases

Investigation of Dipicolinic Acid Isosteres for the Inhibition of Metallo‐β‐Lactamases

β-lactam/β-lactamase inhibitor combinations: an update

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

Contact Info

Product

Resources

About