A fluorogenic substrate of beta-lactamases and its potential as a probe to detect the bacteria resistant to the third-generation oxyimino-cephalosporins

Thai, Hien Bao Dieu; Yu, Jin Kyung; Park, Byung Sun; Park, Yeon-Joon; Min, Sun‐Joon; Ahn, Dae‐Ro

doi:10.1016/j.bios.2015.10.081

Cited by 22 publications

(7 citation statements)

References 26 publications

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“…Because of these difficulties,c onsiderable efforts have been invested in searching for new improved methods that are sensitive, specific,r apid, and cost-effective. Following the successful development of b-lactamase-responsive chromogenica nd fluorogenic molecular probes for the identification of bacterial pathogens, [20][21][22][23][24][25][26][27][28][29] scientists are now actively seekings imilar methods for the specific detectiono fc arbapenemasea nd CPOs.…”

Section: Introductionmentioning

confidence: 99%

Chemiluminescent Carbapenem‐Based Molecular Probe for Detection of Carbapenemase Activity in Live Bacteria

Das

Ihssen²,

Wick³

et al. 2020

Chemistry A European J

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Carbapenemase‐producing organisms (CPOs) pose a severe threat to antibacterial treatment due to the acquisition of antibiotic resistance. This resistance can be largely attributed to the antibiotic‐hydrolyzing enzymes that the bacteria produce. Current carbapenem “wonder drugs”, such as doripenem, ertapenem, meropenem, imipenem, and so on, are resistant to regular β‐lactamases, but susceptible to carbapenemases. Even worse, extended exposure of bacteria to these drugs accelerates the spread of resistance genes. In order to preserve the clinical efficacy of antibacterial treatment, carbapenem drugs should be carefully regulated and deployed only in cases of a CPO infection. Early diagnosis is therefore of paramount importance. Herein, we report the design, synthesis, and activity of the first carbapenemase‐sensitive chemiluminescent probe, CPCL, which may be used to monitor CPO activity. The design of our probe enables enzymatic cleavage of the carbapenem core, which is followed by a facile 1,8‐elimination process and the emission of green light through rapid chemical excitation. We have demonstrated the ability of the probe to detect a number of clinically relevant carbapenemases and the successful identification of CPO present in bacterial cultures, such as those used for clinical diagnosis. We believe that our use of “turn‐on” chemiluminescence activation will find significant application in future diagnostic assays and improve antibacterial treatment.

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Section: Introductionmentioning

confidence: 99%

Chemiluminescent Carbapenem‐Based Molecular Probe for Detection of Carbapenemase Activity in Live Bacteria

Das

Ihssen²,

Wick³

et al. 2020

Chemistry A European J

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“…64 This caging linker strategy significantly improves substrate turnover, as bulky fluorophores directly coupled at the C-3′ position can interfere with BLase binding. 64 Other recent applications developing reporters specific for individual BLases include a ceftazidime-derived N-7 oxyiminocephalosporin, which selectively releases a BODIPY fluorophore in the presence of ESBLs; 65 and carbapenem-based reporters that selectively detect carbapenemases (conjugated BODIPY fluorophore; 66 coumarin probes) 67 and MBLs (umbelliferone fluorophore) 68 (Figure 8D) 2.6. Non-Fluorogenic β-Lactamase Diagnostics.…”

Section: Early Methods For Detectionmentioning

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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“…Resistance predicted by genotypic analysis does not always correlate with phenotypic results, and emerging new mutations may evade nucleic acid-based detection, giving false-negative results. , Substrate-based enzyme function assays can directly reveal whether the bacteria possess the capability to destroy β-lactam antimicrobial activity. Colorimetric, fluorogenic, and Förster resonance energy transfer-based probes have been developed over the years for detecting β-lactamase activity in bacteria. − The cefinase test and the Carba NP test, for example, have been approved for clinical use . However, these assays generally require overnight bacterial culture due to limitations in detection sensitivity or inability to work directly in complex clinical samples.…”

Section: Introductionmentioning

confidence: 99%

Bioluminogenic Probe for Rapid, Ultrasensitive Detection of β-Lactam-Resistant Bacteria

et al. 2023

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Increasingly difficult-to-treat infections by antibiotic-resistant bacteria have become a major public health challenge. Rapid detection of common resistance mechanisms before empiric antibiotic usage is essential for optimizing therapeutic outcomes and containing further spread of resistance to antibiotics among other bacteria. Herein, we present a bioluminogenic probe, D-Bluco, for rapid detection of β-lactamase activity in viable pathogenic bacteria. D-Bluco is a pro-luciferin caged by a β-lactamase-responsive cephalosporin structure and further conjugated with a dabcyl quencher. The caging and quenching significantly decreased the initial background emission and increased the signal-to-background ratio by more than 1200-fold. D-Bluco was shown to detect a broad range of β-lactamases at the femtomolar level. An ultrasensitive RAPID bioluminescence assay using D-Bluco can detect 102 to 103 colony forming unit per milliliter (cfu/mL) of β-lactamase-producing Enterobacterales in urine samples within 30 min. The high sensitivity and rapid detection make the assay attractive for the use of point-of-care diagnostics for lactam-resistant pathogens.

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A fluorogenic substrate of beta-lactamases and its potential as a probe to detect the bacteria resistant to the third-generation oxyimino-cephalosporins

Cited by 22 publications

References 26 publications

Chemiluminescent Carbapenem‐Based Molecular Probe for Detection of Carbapenemase Activity in Live Bacteria

Chemiluminescent Carbapenem‐Based Molecular Probe for Detection of Carbapenemase Activity in Live Bacteria

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

Bioluminogenic Probe for Rapid, Ultrasensitive Detection of β-Lactam-Resistant Bacteria

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