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Helicobacter 2024The current standard treatment for Helicobacter pylori infection, which involves a combination of two broad-spectrum antibiotics, faces significant challenges due to its...
BACKGROUND
The current standard treatment for Helicobacter pylori infection, which involves a combination of two broad-spectrum antibiotics, faces significant challenges due to its detrimental impact on the gut microbiota and the emergence of drug-resistant strains. This underscores the urgent requirement for the development of novel anti-H. pylori drugs. Zoliflodacin, a novel bacterial gyrase inhibitor, is currently undergoing global phase III clinical trials for treating uncomplicated Neisseria gonorrhoeae. However, there is no available data regarding its activity against H. pylori.
MATERIALS AND METHODS
We evaluated the in vitro activity of zoliflodacin against H. pylori clinical isolates (n = 123) with diverse multidrug resistance. We performed DNA gyrase supercoiling and microscale thermophoresis assays to identify the target of zoliflodacin in H. pylori. We analyzed 2262 H. pylori whole genome sequences to identify Asp424Asn and Lys445Asn mutations in DNA gyrase subunit B (GyrB) that are associated with zoliflodacin resistance.
RESULTS
Zoliflodacin exhibits potent activity against all tested isolates, with minimal inhibitory concentration (MIC) values ranging from 0.008 to 1 μg/mL (MIC: 0.125 μg/mL; MIC: 0.25 μg/mL). Importantly, there was no evidence of cross-resistance to any of the four first-line antibiotics commonly used against H. pylori. We identified GyrB as the primary target of zoliflodacin, with Asp424Asn or Lys445Asn substitutions conferring resistance. Screening of 2262 available H. pylori genomes for the two mutations revealed only one clinical isolate carrying Asp424Asn substitution.
CONCLUSION
These findings support the potential of zoliflodacin as a promising candidate for H. pylori treatment, warranting further development and evaluation.
Topics: Humans; Anti-Bacterial Agents; Barbiturates; DNA Gyrase; Drug Resistance, Bacterial; Helicobacter Infections; Helicobacter pylori; Isoxazoles; Microbial Sensitivity Tests; Morpholines; Oxazolidinones; Spiro Compounds; Clinical Trials, Phase III as Topic
PubMed: 38627919
DOI: 10.1111/hel.13075 -
Scientific Reports Apr 2024
PubMed: 38627539
DOI: 10.1038/s41598-024-59332-9 -
Current Drug Discovery Technologies Apr 2024A novel series of 1,3,4‒oxadiazole connected to derivatives of quinazolinone (7a-e and 8a-f) was synthesized in the current investigation, and its anticancer and...
BACKGROUND
A novel series of 1,3,4‒oxadiazole connected to derivatives of quinazolinone (7a-e and 8a-f) was synthesized in the current investigation, and its anticancer and Topoisomerase‒ II inhibitory activity was evaluated.
OBJECTIVE
These findings inspired the design, synthesis, and biological analysis of these 1,3,4‒oxadiazole-quinazolinone analogues as antiproliferative Topo‒II inhibitors.
METHODS
The novel compound structures were determined using mass spectrometry and spectral methods (IR, NMR: 1H & 13C). The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colourimetric assay has been used to evaluate the anticancer efficacy of these drugs, and Autodock 4.2 provides a description of the docking results. For the more active members, additional biological tests, such as the Topo‒II inhibition experiment, were performed. These compounds' physicochemical and ADMET characteristics were examined in more detail.
RESULTS
In the experiment for antiproliferative activity, compounds 7d, 7e, 8c, 8e, and 8f demonstrated encouraging cytotoxicity findings against HCT‒116 and HepG2 cancer cell lines, with IC50 values ranging from 3.85 to 19.43 μM. Compounds 7d, 7e, and 8e were the most potent inhibitors of Topo II with IC50 values of 15.18, 17.55, and 12.59 μM, respectively. Additionally, the docked compound 8c showed the strongest conventional hydrogen bonds among the residues Leu507(B), Asn508(B), Asn520(B), and Glu522(B) in the Human topoisomerase‒IIβ active site in the DNA complex (4G0U) when compared to the findings of docking experiments.
CONCLUSIONS
New findings have discovered the fact that fused 1,3,4‒oxadiazole bearing quinazolinone contributed great significance in the field of medicinal chemistry due to their diverse biological properties. Finally, the in silico pharmacokinetic profile of all the synthesized derivatives was estimated using SwissADME, where some of the compounds followed Lipinski, Veber, Egan, and Muegge rules without deviation. The result of this activity advises that with a simple modification in structure, a potent anticancer agent can be generated with good efficacy.
PubMed: 38616757
DOI: 10.2174/0115701638282655240402042126 -
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 -
FEBS Letters May 2024Evolutionarily conserved protein associated with topoisomerase II (PAT1) proteins activate mRNA decay through binding mRNA and recruiting decapping factors to optimize...
Evolutionarily conserved protein associated with topoisomerase II (PAT1) proteins activate mRNA decay through binding mRNA and recruiting decapping factors to optimize posttranscriptional reprogramming. Here, we generated multiple mutants of pat1, pat1 homolog 1 (path1), and pat1 homolog 2 (path2) and discovered that pat triple mutants exhibit extremely stunted growth and all mutants with pat1 exhibit leaf serration while mutants with pat1 and path1 display short petioles. All three PATs can be found localized to processing bodies and all PATs can target ASYMMETRIC LEAVES 2-LIKE 9 transcripts for decay to finely regulate apical hook and lateral root development. In conclusion, PATs exhibit both specific and redundant functions during different plant growth stages and our observations underpin the selective regulation of the mRNA decay machinery for proper development.
Topics: Arabidopsis; Arabidopsis Proteins; RNA, Messenger; Gene Expression Regulation, Plant; Mutation; RNA Stability
PubMed: 38605280
DOI: 10.1002/1873-3468.14872 -
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 -
Microbiology and Immunology Jun 2024We have previously isolated a gram-negative microaerophilic strain, PAGU2000 from a patient presenting with a fever in Kumamoto Prefecture, Japan. The present study...
We have previously isolated a gram-negative microaerophilic strain, PAGU2000 from a patient presenting with a fever in Kumamoto Prefecture, Japan. The present study aimed to comprehensively analyze the taxonomy of the isolated strain using a polyphasic approach. The 16S rRNA gene sequence analysis indicated that the strain was a member of enterohepatic Helicobacter. The strain PAGU2000 shared a 97.5% 16S rRNA gene nucleotide identity with Helicobacter valdiviensis, and this taxonomic position was confirmed by phylogenetic analysis of the GyrA amino acid sequences. The proposed strain PAGU2000 has a 1.482 Mbp chromosome with a DNA G + C content of 31.3 mol% and encodes 1520 predicted coding sequences. The average nucleotide identity between the strain PAGU2000 and type strain of H. valdiviensis was 70.3%, which was lower than the recommended threshold of 95% for species delineation. The strain PAGU2000 was a motile, non-spore-forming, and spiral-shaped bacterium, exhibiting catalase and oxidase activities but not urease and nitrate reduction. This study demonstrates that the isolate represents a novel species within enterohepatic Helicobacter, for which the name Helicobacter higonensis is proposed (type strain: PAGU2000 = GTC 16811 = LMG 33095). In this study, we describe the phenotypic and morphological features of this strain and propose an emended description of some biochemical traits of H. valdiviensis.
Topics: Helicobacter; RNA, Ribosomal, 16S; Humans; Phylogeny; DNA, Bacterial; Helicobacter Infections; Base Composition; Japan; Sequence Analysis, DNA; Bacterial Typing Techniques; DNA Gyrase
PubMed: 38599769
DOI: 10.1111/1348-0421.13127