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Scientific Reports Apr 2024
PubMed: 38627539
DOI: 10.1038/s41598-024-59332-9 -
Molecules (Basel, Switzerland) Mar 2024Carbothioamides , were generated in high yield by reacting furan imidazolyl ketone with -arylthiosemicarbazide in EtOH with a catalytic amount of conc. HCl. The...
Carbothioamides , were generated in high yield by reacting furan imidazolyl ketone with -arylthiosemicarbazide in EtOH with a catalytic amount of conc. HCl. The reaction of carbothioamides , with hydrazonyl chlorides - in EtOH with triethylamine at reflux produced 1,3-thiazole derivatives -. In a different approach, the 1,3-thiazole derivatives and were produced by reacting and with chloroacetone to afford and , respectively, followed by diazotization with 4-methylbenzenediazonium chloride. The thiourea derivatives and then reacted with ethyl chloroacetate in ethanol with AcONa at reflux to give the thiazolidinone derivatives and . The produced compounds were tested for antioxidant and antibacterial properties. Using phosphomolybdate, promising thiazoles and showed the best antioxidant activities at 1962.48 and 2007.67 µgAAE/g dry samples, respectively. Thiazoles and had the highest antibacterial activity against and with 28, 25 and 27, 28 mm, respectively. Thiazoles and had the best activity against with 26 mm and 37 mm, respectively. Thiazole had the highest activity against , surpassing cyclohexamide. Most compounds demonstrated lower MIC values than neomycin against , and . A molecular docking study examined how antimicrobial compounds interact with DNA gyrase B crystal structures. The study found that all of the compounds had good binding energy to the enzymes and reacted similarly to the native inhibitor with the target DNA gyrase B enzymes' key amino acids.
Topics: Antioxidants; Molecular Docking Simulation; DNA Gyrase; Escherichia coli; Staphylococcus aureus; Anti-Bacterial Agents; Imidazoles; Candida albicans; Thiazoles
PubMed: 38611769
DOI: 10.3390/molecules29071491 -
Molecular Medicine Reports Jun 2024Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the tumour images shown in Fig. 6B on p. 8 were strikingly...
Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the tumour images shown in Fig. 6B on p. 8 were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes, which had either already been published or were under consideration for publication at around the same time. Owing to the fact that the contentious data in the above article were already under consideration for publication prior to its submission to , the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 23: 439, 2021; DOI: 10.3892/mmr.2021.12078].
PubMed: 38606517
DOI: 10.3892/mmr.2024.13218 -
ACS Infectious Diseases Apr 2024Antimicrobial resistance is a global threat to human health. Therefore, efforts have been made to develop new antibacterial agents that address this critical medical...
Antimicrobial resistance is a global threat to human health. Therefore, efforts have been made to develop new antibacterial agents that address this critical medical issue. Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibacterial in clinical development. Recently, phase III clinical trials for gepotidacin treatment of uncomplicated urinary tract infections caused by uropathogens, including , were stopped for demonstrated efficacy. Because of the clinical promise of gepotidacin, it is important to understand how the compound interacts with its cellular targets, gyrase and topoisomerase IV, from . Consequently, we determined how gyrase and topoisomerase IV mutations in amino acid residues that are involved in gepotidacin interactions affect the susceptibility of cells to the compound and characterized the effects of gepotidacin on the activities of purified wild-type and mutant gyrase and topoisomerase IV. Gepotidacin displayed well-balanced dual-targeting of gyrase and topoisomerase IV in cells, which was reflected in a similar inhibition of the catalytic activities of these enzymes by the compound. Gepotidacin induced gyrase/topoisomerase IV-mediated single-stranded, but not double-stranded, DNA breaks. Mutations in GyrA and ParC amino acid residues that interact with gepotidacin altered the activity of the compound against the enzymes and, when present in both gyrase and topoisomerase IV, reduced the antibacterial activity of gepotidacin against this mutant strain. Our studies provide insights regarding the well-balanced dual-targeting of gyrase and topoisomerase IV by gepotidacin in .
Topics: Acenaphthenes; Amino Acids; Anti-Bacterial Agents; DNA Gyrase; DNA Topoisomerase IV; Escherichia coli; Heterocyclic Compounds, 3-Ring
PubMed: 38606465
DOI: 10.1021/acsinfecdis.3c00346 -
ACS Infectious Diseases Apr 2024Fluoroquinolones make up a critically important class of antibacterials administered worldwide to treat human infections. However, their clinical utility has been...
Fluoroquinolones make up a critically important class of antibacterials administered worldwide to treat human infections. However, their clinical utility has been curtailed by target-mediated resistance, which is caused by mutations in the fluoroquinolone targets, gyrase and topoisomerase IV. An important pathogen that has been affected by this resistance is , the causative agent of gonorrhea. Over 82 million new cases of this sexually transmitted infection were reported globally in 2020. Despite the impact of fluoroquinolone resistance on gonorrhea treatment, little is known about the interactions of this drug class with its targets in this bacterium. Therefore, we investigated the effects of the fluoroquinolone ciprofloxacin on the catalytic and DNA cleavage activities of wild-type gyrase and topoisomerase IV and the corresponding enzymes that harbor mutations associated with cellular and clinical resistance to fluoroquinolones. Results indicate that ciprofloxacin interacts with both gyrase (its primary target) and topoisomerase IV (its secondary target) through a water-metal ion bridge that has been described in other species. Moreover, mutations in amino acid residues that anchor this bridge diminish the susceptibility of the enzymes for the drug, leading to fluoroquinolone resistance. Results further suggest that ciprofloxacin primarily induces its cytotoxic effects by enhancing gyrase-mediated DNA cleavage as opposed to inhibiting the DNA supercoiling activity of the enzyme. In conclusion, this work links the effects of ciprofloxacin on wild-type and resistant gyrase to results reported for cellular and clinical studies and provides a mechanistic explanation for the targeting and resistance of fluoroquinolones in .
Topics: Humans; Ciprofloxacin; Fluoroquinolones; DNA Topoisomerase IV; Neisseria gonorrhoeae; Gonorrhea; DNA Gyrase; Microbial Sensitivity Tests
PubMed: 38606464
DOI: 10.1021/acsinfecdis.4c00041 -
Science (New York, N.Y.) Apr 2024DNA supercoiling must be precisely regulated by topoisomerases to prevent DNA entanglement. The interaction of type IIA DNA topoisomerases with two DNA molecules,...
DNA supercoiling must be precisely regulated by topoisomerases to prevent DNA entanglement. The interaction of type IIA DNA topoisomerases with two DNA molecules, enabling the transport of one duplex through the transient double-stranded break of the other, remains elusive owing to structures derived solely from single linear duplex DNAs lacking topological constraints. Using cryo-electron microscopy, we solved the structure of DNA gyrase bound to a negatively supercoiled minicircle DNA. We show how DNA gyrase captures a DNA crossover, revealing both conserved molecular grooves that accommodate the DNA helices. Together with molecular tweezer experiments, the structure shows that the DNA crossover is of positive chirality, reconciling the binding step of gyrase-mediated DNA relaxation and supercoiling in a single structure.
Topics: Cryoelectron Microscopy; DNA; DNA Gyrase; DNA, Superhelical; Escherichia coli; Escherichia coli Proteins; Protein Domains
PubMed: 38603484
DOI: 10.1126/science.adl5899 -
Molecular Therapy. Oncology Mar 2024The high rates of protein synthesis and processing render multiple myeloma (MM) cells vulnerable to perturbations in protein homeostasis. The induction of proteotoxic...
The high rates of protein synthesis and processing render multiple myeloma (MM) cells vulnerable to perturbations in protein homeostasis. The induction of proteotoxic stress by targeting protein degradation with proteasome inhibitors (PIs) has revolutionized the treatment of MM. However, resistance to PIs is inevitable and represents an ongoing clinical challenge. Our first-in-human study of the selective inhibitor of RNA polymerase I transcription of ribosomal RNA genes, CX-5461, has demonstrated a potential signal for anti-tumor activity in three of six heavily pre-treated MM patients. Here, we show that CX-5461 has potent anti-myeloma activity in PI-resistant MM preclinical models and . In addition to inhibiting ribosome biogenesis, CX-5461 causes topoisomerase II trapping and replication-dependent DNA damage, leading to G2/M cell-cycle arrest and apoptotic cell death. Combining CX-5461 with PI does not further enhance the anti-myeloma activity of CX-5461 . In contrast, CX-5461 shows synergistic interaction with the histone deacetylase inhibitor panobinostat in both the Vk∗MYC and the 5T33-KaLwRij mouse models of MM by targeting ribosome biogenesis and protein synthesis through distinct mechanisms. Our findings thus provide strong evidence to facilitate the clinical development of targeting the ribosome to treat relapsed and refractory MM.
PubMed: 38596309
DOI: 10.1016/j.omton.2024.200771 -
Revista Espanola de Quimioterapia :... Jun 2024Mycoplasma genitalium (MG) is a microorganism related to sexually transmitted infections. Antibiotic resistance of MG leads to an increase in treatment failure rates and...
OBJECTIVE
Mycoplasma genitalium (MG) is a microorganism related to sexually transmitted infections. Antibiotic resistance of MG leads to an increase in treatment failure rates and the persistence of the infection. The aim of this study was to describe the most frequent mutations associated with azithromycin and moxifloxacin resistance in our geographical area.
METHODS
A prospective study from May 2019 to May 2023 was performed. MG-positive samples were collected. Real-time PCRs (AllplexTM MG-AziR Assay and AllplexTM MG-MoxiR Assay, Seegene) were performed in MG positive samples to detect mutations in 23S rRNA V domain and parC gene.
RESULTS
A 37.1% of samples presented resistance determinants to azithromycin and the most common mutation detected was A2059G (57.9%). Resistance to moxifloxacin was studied in 72 azithromycin-resistant samples and 36.1% showed mutations, being G248T the most prevalent (73.1%).
CONCLUSIONS
The resistance to different lines of treat ment suggests the need for a targeted therapy and the performing of a test of cure afterwards.
Topics: Mycoplasma genitalium; Moxifloxacin; Azithromycin; Spain; Humans; Prospective Studies; Anti-Bacterial Agents; Drug Resistance, Bacterial; Mycoplasma Infections; Mutation; Female; Male; Microbial Sensitivity Tests; RNA, Ribosomal, 23S; Adult; DNA Topoisomerase IV
PubMed: 38591493
DOI: 10.37201/req/015.2024 -
Cell Reports Apr 2024In the search for much-needed new antibacterial chemical matter, a myriad of compounds have been reported in academic and pharmaceutical screening endeavors. Only a...
In the search for much-needed new antibacterial chemical matter, a myriad of compounds have been reported in academic and pharmaceutical screening endeavors. Only a small fraction of these, however, are characterized with respect to mechanism of action (MOA). Here, we describe a pipeline that categorizes transcriptional responses to antibiotics and provides hypotheses for MOA. 3D-printed imaging hardware PFIboxes) profiles responses of Escherichia coli promoter-GFP fusions to more than 100 antibiotics. Notably, metergoline, a semi-synthetic ergot alkaloid, mimics a DNA replication inhibitor. In vitro supercoiling assays confirm this prediction, and a potent analog thereof (MLEB-1934) inhibits growth at 0.25 μg/mL and is highly active against quinolone-resistant strains of methicillin-resistant Staphylococcus aureus. Spontaneous suppressor mutants map to a seldom explored allosteric binding pocket, suggesting a mechanism distinct from DNA gyrase inhibitors used in the clinic. In all, the work highlights the potential of this platform to rapidly assess MOA of new antibacterial compounds.
Topics: Topoisomerase II Inhibitors; DNA Gyrase; Anti-Bacterial Agents; Escherichia coli; Transcription, Genetic; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests
PubMed: 38578824
DOI: 10.1016/j.celrep.2024.114053 -
Brain Communications 2024Alzheimer's disease accounts for 60-70% of dementia cases. Current treatments are inadequate and there is a need to develop new approaches to drug discovery. Recently,...
Alzheimer's disease accounts for 60-70% of dementia cases. Current treatments are inadequate and there is a need to develop new approaches to drug discovery. Recently, in cancer, morphological profiling has been used in combination with high-throughput screening of small-molecule libraries in human cells . To test feasibility of this approach for Alzheimer's disease, we developed a cell morphology-based drug screen centred on the risk gene, (which encodes the protein SORLA). Increased Alzheimer's disease risk has been repeatedly linked to variants in , particularly those conferring loss or decreased expression of SORLA, and lower levels are observed in post-mortem brain samples from individuals with Alzheimer's disease. Consistent with its role in the endolysosomal pathway, deletion is associated with enlarged endosomes in neural progenitor cells and neurons. We, therefore, hypothesized that multi-parametric, image-based cell phenotyping would identify features characteristic of deletion. An automated morphological profiling method (Cell Painting) was adapted to neural progenitor cells and used to determine the phenotypic response of neural progenitor cells to treatment with compounds from a small internationally approved drug library (TargetMol, 330 compounds). We detected distinct phenotypic signatures for neural progenitor cells compared to isogenic wild-type controls. Furthermore, we identified 16 compounds (representing 14 drugs) that reversed the mutant morphological signatures in neural progenitor cells derived from three induced pluripotent stem cell sub-clones. Network pharmacology analysis revealed the 16 compounds belonged to five mechanistic groups: 20S proteasome, aldehyde dehydrogenase, topoisomerase I and II, and DNA synthesis inhibitors. Enrichment analysis identified DNA synthesis/damage/repair, proteases/proteasome and metabolism as key pathways/biological processes. Prediction of novel targets revealed enrichment in pathways associated with neural cell function and Alzheimer's disease. Overall, this work suggests that (i) a quantitative phenotypic metric can distinguish induced pluripotent stem cell-derived neural progenitor cells from isogenic wild-type controls and (ii) phenotypic screening combined with multi-parametric high-content image analysis is a viable option for drug repurposing and discovery in this human neural cell model of Alzheimer's disease.
PubMed: 38576795
DOI: 10.1093/braincomms/fcae101