The main protease (M) of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) represents a promising target for antiviral drugs aimed at combating COVID-19. Consequently, the development of M inhibitor is an ideal strategy for combating the virus. In this study, we identified twenty-two dithiocarbamates (1 a-h), dithiocarbamate-Cu(II) complexes (2 a-hCu) and disulfide derivatives (2 a-e, 2 i) as potent inhibitors of M, with IC value range of 0.
View Article and Find Full Text PDFThe bacterial infection mediated by β-lactamases MβLs and SβLs has grown into an emergent health threat, however, development of a molecule that dual inhibits both MβLs and SβLs is challenging. In this work, a series of hydroxamates 1a-g, 2a-e, 3a-c, 4a-c were synthesized, characterized by H and C NMR and confirmed by HRMS. Biochemical assays revealed that these molecules dually inhibited MβLs (NDM-1, IMP-1) and SβLs (KPC-2, OXA-48), with an IC value in the range of 0.
View Article and Find Full Text PDFInt J Biol Macromol
December 2023
Metallo-carbapenemases-mediated carbapenem-resistant Enterobacterales (CREs) has been acknowledged as "urgent threat" by the World Health Organization. The discovery of new strategies that block metallo-carbapenemases activity to reverse carbapenem resistance is an urgent need. In this study, a coumarin copper complex containing a PEG linker and glucose ligand, GluC-Cu, was used to reverse carbapenem resistance.
View Article and Find Full Text PDFThe continuous emergence of multi-drug resistant pathogens co-expressing serine and metallo-carbapenemases seriously threatens the efficacy of carbapenem. Here, we report the first SeCN-derived dual inhibitor of serine and metallo-carbapenemases with IC values ranging from 0.0038 to 1.
View Article and Find Full Text PDFMultidrug-resistant bacterial infections mediated by metallo-β-lactamases (MβLs) have grown into an emergent health threat, and development of novel antimicrobials is an ideal strategy to combat the infections. Herein, a novel vancomycin derivative was constructed by conjugation of triazolylthioacetamide and vancomycin molecules, characterized by reverse-phase high performance liquid chromatography (HPLC) and confirmed by matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS). The biological assays revealed that effectively inhibited and methicillin-resistant (MRSA), gradually increased the antimicrobial effect of β-lactam antibiotics (cefazolin, meropenem and penicillin G) and exhibited a dose-dependent synergistic antibacterial effect against eight resistant strains tested, which was confirmed by the time-kill curves determination.
View Article and Find Full Text PDFThe overuse of antibiotics exacerbates the development of antibiotic-resistant bacteria, threatening global public health, while most traditional antibiotics act on specific targets and sterilize through chemical modes. Therefore, it is a desperate need to design novel therapeutics or extraordinary strategies to overcome resistant bacteria. Herein, we report a positively charged nanocomposite PNs-Cur with a hydrodynamic diameter of 289.
View Article and Find Full Text PDFMetallo-β-lactamases (MβLs) hydrolyze almost all β-lactam antibiotics, including last-resort carbapenems, and is emerging as a global antibiotic resistance threat. Discovering novel fluorescent molecules for visualizing MβLs has proved challenging. Herein, based on covalent and Zn(II)-binding scaffold of MβLs inhibitor, we designed and synthesized a novel series of environment-sensitive fluorescent probes ESA, DHA and DHS, to detect and inhibit the enzymatic activity of MβLs.
View Article and Find Full Text PDFThe superbug infection mediated by metallo-β-lactamases (MβLs) has grown into anemergent health threat, and development of MβL inhibitors is an ideal strategy to combat the infection. In this work, twenty-five thiosemicarbazones 1a-e, 2a-e, 3a-e, 4a-d, 5a-d and 6a-b were synthesized and assayed against MβLs ImiS, NDM-1 and L1. The gained molecules specifically inhibited NDM-1 and ImiS, exhibiting an IC value in the range of 0.
View Article and Find Full Text PDFThe irregular use of antibiotics has created a natural selection pressure for bacteria to adapt resistance. Bacterial resistance caused by metallo-β-lactamases (MβLs) has been the most prevalent in terms of posing a threat to human health. The New Delhi metallo-β-lactamase-1 (NDM-1) has been shown to be capable of hydrolyzing almost all β-lactams.
View Article and Find Full Text PDFThe emerging COVID-19 pandemic generated by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has severely threatened human health. The main protease (M) of SARS-CoV-2 is promising target for antiviral drugs, which plays a vital role for viral duplication. Development of the inhibitor against M is an ideal strategy to combat COVID-19.
View Article and Find Full Text PDFSerine/metallo-carbapenemase-coproducing pathogens, often referred to as "superbugs", are a significant clinical problem. They hydrolyze nearly all available β-lactam antibiotics, especially carbapenems considered as last-resort antibiotics, seriously endangering efficacious antibacterial treatment. Despite the continuous global spread of carbapenem resistance, no dual-action inhibitors are available in therapy.
View Article and Find Full Text PDFThe "superbug" infection caused by metallo-β-lactamases (MβLs) has grown into anemergent health threat, and development of effective MβL inhibitors to restore existing antibiotic efficacy is an ideal alternative. Although the serine-β-lactamase inhibitors have been used in clinical settings, MβL inhibitors are not available to date. In this work, thirty-one quinolinyl sulfonamides 1a-p and sulphonyl esters 2a-o were synthesized and assayed against MβL NDM-1.
View Article and Find Full Text PDFChem Biol Drug Des
February 2022
Bacterial resistance caused by metallo-β-lactamases (MβLs) has become an emerging public health threat, and the development of MβLs inhibitor is an effective way to overcome the resistance. In this study, thirteen novel O-aryloxycarbonyl hydroxamates were constructed and assayed against MβLs. The obtained molecules specifically inhibited imipenemase-1 (IMP-1) and New Delhi metallo-β-lactamase-1, exhibiting an IC value in the range of 0.
View Article and Find Full Text PDFThe worldwide prevalence of NDM-1-producing Gram-negative pathogens has drastically undermined the clinical efficacy of carbapenems, prompting a need to devise an effective strategy to preserve their clinical value. Here we constructed a focused compound library of dithiocarbamates and systematically evaluated their potential synergistic antibacterial activities combined with copper. SA09-Cu exhibited excellent inhibition against a series of clinical NDM-1-producing carbapenem-resistant Enterobacteriaceae (CRE) in restoring meropenem effect, and slowed down the development of carbapenem resistance.
View Article and Find Full Text PDFJ Antibiot (Tokyo)
September 2021
The superbug infection caused by metallo-β-lactamases (MβLs) carrying drug-resistant bacteria, specifically, New Delhi metallo-β-lactamase (NDM-1) has become an emerging threat. In an effort to develop novel inhibitors of NDM-1, thirteen thiosemicarbazones (1a-1m) were synthesized and assayed. The obtained molecules specifically inhibited NDM-1, with an IC in the range of 0.
View Article and Find Full Text PDFThe expression of β-lactamases, especially metallo-β-lactamases (MβLs) in bacteria is one of the main causes of drug resistance. In this work, an effective N-acylhydrazone scaffold as MβL inhibitor was constructed and characterized. The biological activity assays indicated that the synthesized N-acylhydrazones 1-11 preferentially inhibited MβL NDM-1, and 1 was found to be the most effective inhibitor with an IC of 1.
View Article and Find Full Text PDFThe emerging COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has raised a global catastrophe. To date, there is no specific antiviral drug available to combat this virus, except the vaccine. In this study, the main protease (M) required for SARS-CoV-2 viral replication was expressed and purified.
View Article and Find Full Text PDFTo combat the superbug infection caused by metallo-β-lactamases (MβLs), a dipyridyl-substituted thiosemicarbazone (DpC), was identified to be the broad-spectrum inhibitor of MβLs (NDM-1, VIM-2, IMP-1, ImiS, L1), with an IC value in the range of 0.021-1.08 µM.
View Article and Find Full Text PDFMetallo-β-lactamase (MβL) ImiS contributes to the emergence of carbapenem resistance. A potent scaffold, -substituted benzenesulfonamide, was constructed and assayed against MβLs. The twenty-one obtained molecules specifically inhibited ImiS (IC = 0.
View Article and Find Full Text PDFThe superbug infection caused by New Delhi metallo-β-lactamase (NDM-1) has become an emerging public health threat. Inhibition of NDM-1 has proven challenging due to its shuttling between pathogenic bacteria. A potent scaffold, diaryl-substituted thiosemicarbazone, was constructed and assayed with metallo-β-lactamases (MβLs).
View Article and Find Full Text PDFGiven that β-lactam antibiotic resistance mediated by metallo-β-lactamases (MβLs) seriously threatens human health, we designed and synthesized nineteen hydroxamic acids with benzenesulfonamide, which exhibited broad-spectrum inhibition against four tested MβLs ImiS, L1, VIM-2 and IMP-1 (except 6, 13 and 18 on IMP-1, and 18 on VIM-2), with an IC value in the range of 0.6-9.4, 1.
View Article and Find Full Text PDFMetallo-β-lactamase (MBL)-producing bacteria resistant to β-lactam antibiotics are a serious threat to human health. Despite great efforts and important progress in the discovery of MBL inhibitors (MBLIs), there is none in clinical use. Herein, inhibitor complexes of the MBL CcrA were investigated by NMR spectroscopy to provide perspectives on the further development of 2-(triazolylthio)acetamide-type MBLIs.
View Article and Find Full Text PDFEur J Med Chem
October 2020
The emergence and prevalence of metallo-β-lactamases (MβLs)-mediated bacterial resistance has seriously threatened the global health today. MβLs are deemed to be one of the most worrying bacterial resistance factors that hydrolyze nearly all β-lactam antibiotics. However, none of MβL inhibitors have appeared in clinic to date.
View Article and Find Full Text PDFThe emergence and prevalence of carbapenem-resistant bacterial infection have seriously threatened the clinical use of almost all β-lactam antibacterials. The development of effective metallo-β-lactamase (MβL) inhibitors to restore the existing antibiotics efficacy is an ideal alternative. Although several types of serine-β-lactamase inhibitors have been successfully developed and used in clinical settings, MβL inhibitors are not clinically available to date.
View Article and Find Full Text PDFAntibiotics (Basel)
February 2020
Metallo-β-lactamase (MβLs) mediated antibiotic resistance seriously threatens the treatment of bacterial diseases. Recently, we found that thioacetamides can be a potential MβL inhibitor skeleton. In order to improve the information of the skeleton, twelve new thiazolethioacetamides were designed by modifying the aromatic substituent.
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