A novel fluorogenic substrate for dinuclear Zn(II)-containing metallo-β-lactamases

Yin-lin, Zhang; Xiao, Ji‐Chang; Feng, Jian; Yang, Ke‐Wu; Feng, Lei; Zhou, Lisheng; Crowder, Michael W.

doi:10.1016/j.bmcl.2013.01.071

Cited by 12 publications

(3 citation statements)

References 25 publications

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“…Several screening methods for the in vitro and in vivo detection of β-lactamases have been reported . Representative substrates currently in use for β-lactamases include chromogenic cephalosporin-based substrates, such as CENTA, PADAC, and nitrocefin, cephalosporin-based fluorogenic substrates, bioluminescent probes, and fluorescence resonance energy transfer (FRET)-based substrates . These substrates have mainly been applied in research centered around SBLs and only in one case on MBLs (L1 and CcrA) .…”

Section: Resultsmentioning

confidence: 99%

Assay Platform for Clinically Relevant Metallo-β-lactamases

et al. 2013

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Metallo-β-lactamases (MBLs) are a growing threat to the use of almost all clinically used β-lactam antibiotics. The identification of broad-spectrum MBL inhibitors is hampered by the lack of a suitable screening platform, consisting of appropriate substrates and a set of clinically relevant MBLs. We report procedures for the preparation of a set of clinically relevant metallo-β-lactamases (i.e., NDM-1 (New Delhi MBL), IMP-1 (Imipenemase), SPM-1 (São Paulo MBL), and VIM-2 (Verona integron-encoded MBL)) and the identification of suitable fluorogenic substrates (umbelliferone-derived cephalosporins). The fluorogenic substrates were compared to chromogenic substrates (CENTA, nitrocefin, and imipenem), showing improved sensitivity and kinetic parameters. The efficiency of the fluorogenic substrates was exemplified by inhibitor screening, identifying 4-chloroisoquinolinols as potential pan MBL inhibitors.

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Section: Resultsmentioning

confidence: 99%

Assay Platform for Clinically Relevant Metallo-β-lactamases

et al. 2013

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“…This new strategy was successfully applied to image TEM-1/fLuc-transfected COS7 cells in a live mouse model following intravenous Bluco administration . Similar, simple fluorophore-releasing probes have been employed for a number of applications, including monitoring of S. aureus with a near-infrared hemicyanine fluorophore, as well as fluorogenic substrates of MBLs and TEM-1. − …”

Section: Imaging: Lactam-based Probes and Their Applicationsmentioning

confidence: 99%

β-Lactamase-Mediated Fragmentation: Historical Perspectives and Recent Advances in Diagnostics, Imaging, and Antibacterial Design

2022

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The discovery of β-lactam (BL) antibiotics in the early 20th century represented a remarkable advancement in human medicine, allowing for the widespread treatment of infectious diseases that had plagued humanity throughout history. Yet, this triumph was followed closely by the emergence of β-lactamase (BLase), a bacterial weapon to destroy BLs. BLase production is a primary mechanism of resistance to BL antibiotics, and the spread of new homologues with expanded hydrolytic activity represents a pressing threat to global health. Nonetheless, researchers have developed strategies that take advantage of this defense mechanism, exploiting BLase activity in the creation of probes, diagnostic tools, and even novel antibiotics selective for resistant organisms. Early discoveries in the 1960s and 1970s demonstrating that certain BLs expel a leaving group upon BLase cleavage have spawned an entire field dedicated to employing this selective release mechanism, termed BLase-mediated fragmentation. Chemical probes have been developed for imaging and studying BLase-expressing organisms in the laboratory and diagnosing BL-resistant infections in the clinic. Perhaps most promising, new antibiotics have been developed that use BLase-mediated fragmentation to selectively release cytotoxic chemical "warheads" at the site of infection, reducing offtarget effects and allowing for the repurposing of putative antibiotics against resistant organisms. This Review will provide some historical background to the emergence of this field and highlight some exciting recent reports that demonstrate the promise of this unique release mechanism.

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“…A number of groups, including ours, have reported other chromogenic (CENTA [4], Cefesone (S1) [5], HMRZ-86 [6], PADAC [7], CLS405 [8], Chromacef [9]), and fluorogenic substrates, Ghavami et al Assay for drug discovery 4 (CA [10]; FC-3 to FC-5 [11]), and, recently, a near-infrared fluorescent probe [12]); some of which have advantages over nitrocefin in certain applications.…”

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confidence: 99%