The Development of New Small-Molecule Inhibitors Targeting Bacterial Metallo-β-lactamases

Wang, Ping; Cheng, Jing; Liu, Congcong; Tang, Kai; Xing, Feng; Yu, Zhiqiang; Yu, Bin; Chang, Junbiao

doi:10.2174/1568026618666180518101028

Cited by 6 publications

(3 citation statements)

References 89 publications

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“…Therefore, MBL inhibition is often focused on the binding of Zn ions. Several structurally diverse classes such as dicarboxylic acids [116], triazoles [116], phosphonates, boronates, and thiol-based MBL inhibitors, [23] have been synthesized and explored to determine their enzyme inhibition activity, and the literature describing these classes has been extensively reviewed recently [117]. We will focus on the newly emerging classes of compounds that have not yet been reviewed.…”

Section: Cyclic Boronatesmentioning

confidence: 99%

Recent Developments to Cope the Antibacterial Resistance via β-Lactamase Inhibition

et al. 2022

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Antibacterial resistance towards the β-lactam (BL) drugs is now ubiquitous, and there is a major global health concern associated with the emergence of new β-lactamases (BLAs) as the primary cause of resistance. In addition to the development of new antibacterial drugs, β-lactamase inhibition is an alternative modality that can be implemented to tackle this resistance channel. This strategy has successfully revitalized the efficacy of a number of otherwise obsolete BLs since the discovery of the first β-lactamase inhibitor (BLI), clavulanic acid. Over the years, β-lactamase inhibition research has grown, leading to the introduction of new synthetic inhibitors, and a few are currently in clinical trials. Of note, the 1, 6-diazabicyclo [3,2,1]octan-7-one (DBO) scaffold gained the attention of researchers around the world, which finally culminated in the approval of two BLIs, avibactam and relebactam, which can successfully inhibit Ambler class A, C, and D β-lactamases. Boronic acids have shown promise in coping with Ambler class B β-lactamases in recent research, in addition to classes A, C, and D with the clinical use of vaborbactam. This review focuses on the further developments in the synthetic strategies using DBO as well as boronic acid derivatives. In addition, various other potential serine- and metallo- β-lactamases inhibitors that have been developed in last few years are discussed briefly as well. Furthermore, binding interactions of the representative inhibitors have been discussed based on the crystal structure data of inhibitor-enzyme complex, published in the literature.

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Section: Cyclic Boronatesmentioning

confidence: 99%

Recent Developments to Cope the Antibacterial Resistance via β-Lactamase Inhibition

et al. 2022

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“…The thiol group is known to be a zinc chelator, and it is therefore not surprising that this moiety is commonly found in programs aimed at identifying novel inhibitors against class B β-lactamases. − The most revelant examples reported to date are summarized in Figure . Klingler et al screened 11 approved drugs or their bioactive metabolites containing a free thiol group, and they identified four drugs that inhibit the clinically relevant metallo-β-lactamases NDM-1, VIM-1, and IMP-7 (Figure A).…”

Section: Non-β-lactam β-Lactamase Inhibitorsmentioning

confidence: 99%

β-Lactamase Inhibitors To Restore the Efficacy of Antibiotics against Superbugs

et al. 2019

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Infections caused by resistant bacteria are nowadays too common, and some pathogens have even become resistant to multiple types of antibiotics, in which case few or even no treatments are available. In recent years, the most successful strategy in anti-infective drug discovery for the treatment of such problematic infections is the combination therapy "antibiotic + inhibitor of resistance". These inhibitors allow the repurposing of antibiotics that have already proven to be safe and effective for clinical use. Three main types of compounds have been developed to block the principal bacterial resistance mechanisms: (i) β-lactamase inhibitors; (ii) outer membrane permeabilizers; (iii) efflux pump inhibitors. This Perspective is focused on β-lactamase inhibitors that disable the most prevalent cause of antibiotic resistance in Gram-negative bacteria, i.e., the deactivation of the most widely used antibiotics, β-lactams (penicillins, cephalosporines, carbapenems, and monobactams), by the production of βlactamases. An overview of the most recently identified β-lactamase inhibitors and of combination therapy is provided. The article also covers the mechanism of action of the different types of β-lactamase enzymes as a basis for inhibitor design and target inactivation.

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“…Pyrrole/furan/thiophene derivatives, the nitrogen/oxygen/sulfur‐containing heterocycles, are potential inhibitors of tyrosinase, [ 112 ] DNA gyrase, topoisomerase IV, [ 113,114 ] tyrosyl‐tRNA synthetase, [ 115 ] efflux pump, [ 116 ] and metallo‐β‐lactamases. [ 117 ] Thus, the pyrrole/furan/thiophene derivatives possess an excellent activity against both drug‐sensitive and ‐resistant, even multidrug‐resistant, pathogens. [ 118,119 ] Moreover, many pyrrole/furan/thiophene‐containing derivatives, such as cefoxitin and temocillin, are common antibacterial agents used in clinics.…”

Section: Indole/isatin–pyrrole/furan/thiophene Hybridsmentioning

confidence: 99%

Indole/isatin‐containing hybrids as potential antibacterial agents

Song

Bian

et al. 2020

Archiv der Pharmazie

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The emergence and worldwide spread of drug-resistant bacteria have already posed a serious threat to human life, creating the urgent need to develop potent and novel antibacterial drug candidates with high efficacy. Indole and isatin (indole-2,3-dione) present a wide structural and mechanistic diversity, so their derivatives possess various pharmacological properties and occupy a salient place in the development of new drugs. Indole/isatin-containing hybrids, which demonstrate a promising activity against a panel of clinically important Gram-positive and Gram-negative bacteria, are privileged scaffolds for the discovery of novel antibacterial candidates. This review, covering articles published between January 2015 and May 2020, focuses on the development and structure-activity relationship (SAR) of indole/isatincontaining hybrids with potential application for fighting bacterial infections, to facilitate further rational design of novel drug candidates.

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The Development of New Small-Molecule Inhibitors Targeting Bacterial Metallo-β-lactamases

Cited by 6 publications

References 89 publications

Recent Developments to Cope the Antibacterial Resistance via β-Lactamase Inhibition

Recent Developments to Cope the Antibacterial Resistance via β-Lactamase Inhibition

β-Lactamase Inhibitors To Restore the Efficacy of Antibiotics against Superbugs

Indole/isatin‐containing hybrids as potential antibacterial agents

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