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Journal of Microbiological Methods Jun 2024In radiation-resistant bacteria belonging to the genus Deinococcus, transposition events of insertion sequences (IS elements) leading to phenotypic changes from a...
In radiation-resistant bacteria belonging to the genus Deinococcus, transposition events of insertion sequences (IS elements) leading to phenotypic changes from a reddish color to white were detected following exposure to gamma irradiation and hydrogen peroxide treatment. This change resulted from the integration of IS elements into the phytoene desaturase gene, a key enzyme in the carotenoid biosynthesis pathway. To facilitate species identification and distinguish among Deinococcus strains, the gyrB gene encoding the B subunit of DNA gyrase was utilized. The s gnificance of the gyrB gene is well recognized not only in genome replication through the regulation of supercoiling but also in phylogenetic analysis providing support for 16S rRNA-based identification. Its mutation rate surpasses that of the 16S rRNA gene, offering greater resolution between closely related species, particularly those exhibiting >99% similarity. In this study, phylogenetic analysis was conducted comparing the 16S rRNA and gyrB gene sequences of Deinococcus species. Species-specific and genus-specific primers targeting Deinococcus species were designed and experimentally validated for selective amplification and rapid identification of the targeted species. This approach allows for the omission of 16S rRNA sequencing in the targeted Deinococcus species. Therefore, the gyrB gene is useful for identifying bacterial species and genus-level detection from individual microbes or microbial consortia using specialized primer sets for PCR amplification.
PubMed: 38936431
DOI: 10.1016/j.mimet.2024.106980 -
Frontiers in Chemistry 2024DNA gyrase and topoisomerase IV show great potential as targets for antibacterial medicines. In recent decades, various categories of small molecule inhibitors have been...
DNA gyrase and topoisomerase IV show great potential as targets for antibacterial medicines. In recent decades, various categories of small molecule inhibitors have been identified; however, none have been effective in the market. For the first time, we developed a series of disalicylic acid methylene/Schiff bases hybrids () to act as antibacterial agents targeting DNA gyrase and topoisomerase IV. The findings indicated that the new targets exhibited significant antibacterial activity against Gram-positive and Gram-negative bacteria, with efficacy ranging from 75% to 115% of the standard ciprofloxacin levels. Compound demonstrated the greatest efficacy compared to the other compounds tested, with minimum inhibitory concentration (MIC) values of 0.030, 0.065, and 0.060 μg/mL against , , and . had a MIC value of 0.050 μg/mL against , which is five times less potent than ciprofloxacin. The inhibitory efficacy of the most potent antibacterial derivatives , , , and against DNA gyrase was assessed. The tested compounds demonstrated inhibitory effects on DNA gyrase, with IC values ranging from 92 to 112 nM. These results indicate that , , , and are more effective than the reference novobiocin, which had an IC value of 170 nM. Compounds , , , and were subjected to additional assessment against topoisomerase IV. Compounds and , which have the highest efficacy in inhibiting gyrase, also demonstrated promising effects on topoisomerase IV. Compounds and exhibit IC values of 3.50 µM and 5.80 µM, respectively. These results are much lower and more potent than novobiocin's IC value of 11 µM. Docking studies demonstrate the potential of compound as an effective dual inhibitor against DNA gyrase and topoisomerase IV, with ADMET analysis indicating promising pharmacokinetic profiles for antibacterial drug development.
PubMed: 38911996
DOI: 10.3389/fchem.2024.1419242 -
RSC Advances Jun 2024In this study, nickel selenide (NiSe), Ag/CN-NiSe, and CN/Ag-NiSe nanowires (NWs) were synthesized coprecipitation. The prepared NWs were employed for the degradation...
In this study, nickel selenide (NiSe), Ag/CN-NiSe, and CN/Ag-NiSe nanowires (NWs) were synthesized coprecipitation. The prepared NWs were employed for the degradation of the rhodamine B (RhB) dye in the absence of light using sodium borohydride (NaBH), bactericidal activity against pathogenic () and docking study to investigate the d-alanine ligase (DDl) and deoxyribonucleic acid (DNA) gyrase of . NWs demonstrate a catalytic degradation efficiency of 69.58% toward RhB in a basic medium. The percentage efficacy of the synthesized materials was evaluated as 19.12-42.62% at low and 36.61-49.72% at high concentrations against pathogenic . Molecular docking results suggest that both CN/Ag-doped NiSe and Ag/CN-doped NiSe possess inhibitory activities toward DDl and DNA gyrase of , which coincides with the bactericidal activity. Based on the research outcomes, the synthesized NWs show potential as an effective agent for water purification and resistance to microbial contaminants.
PubMed: 38911830
DOI: 10.1039/d4ra01437e -
Current Drug Discovery Technologies Jun 2024The development of antimicrobial agents is crucial for several reasons, primarily to combat infectious diseases and to address the growing threat of antimicrobial...
BACKGROUND
The development of antimicrobial agents is crucial for several reasons, primarily to combat infectious diseases and to address the growing threat of antimicrobial resistance. The need for the contin-ued development of antimicrobial drugs persists despite the presence of many existing drugs for several reasons viz; emerging new pathogens and diseases, reistance to existing drug and propogation of multi-drug resistance to existing drugs.
OBJECTIVE
The objective of the study was to synthesize and evaluate the antimicrobial potential of newly synthesized benzothiazole derivatives.
METHODS
A new series of 2-(substituted amino)-N-(6-substituted-1,3-benzothiazol-2yl)acetamide BTC(a-t) has been synthesized by reacting it with chloracetyl chloride with substituted 2-amino benzothiazole and further refluxed with various substituted amines to obtain target compounds. The synthesized compounds were screened experimentally for their antimicrobial property against gram-positive and gram-negative bacteria and fungi. The zone of inhibition and minimum inhibitory concentration of compounds were determined against selected bacterial and fungal strains. Further docking study was carried out to check the probable interactions with the selected protein using V-life MDS 3.5 software (DNA gyrase, PDB: 3G75).
RESULT
Compounds BTC-j N-(6-methoxy-1,3-benzothiazol-2-yl)-2-(pyridine-3-ylamino)acetamide and BTC-r N-(6-nitro-1,3-benzothiazol-2-yl)-2-(pyridine-3-ylamino)acetamide were found to have good antimicrobial potential. The compound BTC-j showed good antibacterial activity against S. aureus at an MIC value of 12.5 μg/mL, B. subtilis at MIC of 6.25μg/mL, E. coli at MIC of 3.125μg/mL, and P. aeruginosa at MIC of 6.25μg/mL. Thus, from the result, it was observed that compounds BTC-j, BTC-f, BTC-n, and BTC-r exhibited significant antibacterial and antifungal potential at different concentrations.
CONCLUSION
The present study resulted in the successful synthesis of 2-acetamido substituted benzothiazole derivatives BTC(a-t) with good yields. The dock score of the compounds and the antimicrobial activity were found to be consistent. No statistical difference in the antimicrobial activity of the standard and test compounds was found, indicating that the test compounds have comparable activity. Therefore, benzothiazole linked to heterocyclic rings with an acetamide linkage may serve as promising lead molecules for further optimization in the journey to discover potent antibacterial agents. Thus, we conclude that the synthesized compounds have the potential for further development as novel antimicrobial agents.
PubMed: 38910468
DOI: 10.2174/0115701638299377240604112400 -
Current Microbiology Jun 2024Zoliflodacin is a spiropyrimidinetrione antibiotic that acts by binding to the GyrB part of the DNA gyrase enzyme in bacteria. Its effectiveness for the treatment of...
Zoliflodacin is a spiropyrimidinetrione antibiotic that acts by binding to the GyrB part of the DNA gyrase enzyme in bacteria. Its effectiveness for the treatment of Neisseria gonorrhoeae infections has been investigated extensively. Since antibiotic resistance has been reached an alarming rate worldwide, researches on new antimicrobials are considered a priority, especially in the treatment of multidrug-resistant Gram-negative bacteria, such as Klebsiella pneumonia. The aim of this study is to test and compare the effectiveness of zoliflodacin with some traditional antibiotics which are frequently preferred in the treatment of Gram-negative pathogens, primarily K. pneumonia. Additionally, its ability to prevent biofilm formation has also been determined. The minimum inhibitory concentration (MIC) values of zoliflodacin along with levofloxacin, meropenem, gentamicin, ampicillin/sulbactam and ceftazidime/avibactam were evaluated by broth microdilution method against 15 Gram-negative clinical isolates and three standard strains. Also, the synergism potential of zoliflodacin with other antibiotics was evaluated by the checkerboard method against standard strains of K. pneumonia, Pseudomonas aeruginosa, and Acinetobacter baumannii. In addition, the inhibitory effects of zoliflodacin on biofilm formation of standard strains were determined. Zoliflodacin MICs were found to be in the range of 2-64 µg/mL, and its combination with meropenem and ampicillin/sulbactam was found to be synergistic, especially against A. baumannii. Zoliflodacin significantly inhibited A. baumannii biofilm at sub-MIC values. These results indicated that zoliflodacin can be considered as an alternative against infections of Gram-negative pathogens, alone or in combination.
Topics: Anti-Bacterial Agents; Microbial Sensitivity Tests; Gram-Negative Bacteria; Biofilms; Humans; Drug Synergism; Oxazolidinones; Klebsiella pneumoniae; Gram-Negative Bacterial Infections; Barbiturates; Isoxazoles; Morpholines; Spiro Compounds
PubMed: 38910195
DOI: 10.1007/s00284-024-03761-2 -
Bioorganic & Medicinal Chemistry Jul 2024N-(Benzothiazole-2-yl)pyrrolamide DNA gyrase inhibitors with benzyl or phenethyl substituents attached to position 3 of the benzothiazole ring or to the carboxamide...
Exploring the interaction of N-(benzothiazol-2-yl)pyrrolamide DNA gyrase inhibitors with the GyrB ATP-binding site lipophilic floor: A medicinal chemistry and QTAIM study.
N-(Benzothiazole-2-yl)pyrrolamide DNA gyrase inhibitors with benzyl or phenethyl substituents attached to position 3 of the benzothiazole ring or to the carboxamide nitrogen atom were prepared and studied for their inhibition of Escherichia coli DNA gyrase by supercoiling assay. Compared to inhibitors bearing the substituents at position 4 of the benzothiazole ring, the inhibition was attenuated by moving the substituent to position 3 and further to the carboxamide nitrogen atom. A co-crystal structure of (Z)-3-benzyl-2-((4,5-dibromo-1H-pyrrole-2-carbonyl)imino)-2,3-dihydrobenzo[d]-thiazole-6-carboxylic acid (I) in complex with E. coli GyrB24 (ATPase subdomain) was solved, revealing the binding mode of this type of inhibitor to the ATP-binding pocket of the E. coli GyrB subunit. The key binding interactions were identified and their contribution to binding was rationalised by quantum theory of atoms in molecules (QTAIM) analysis. Our study shows that the benzyl or phenethyl substituents bound to the benzothiazole core interact with the lipophilic floor of the active site, which consists mainly of residues Gly101, Gly102, Lys103 and Ser108. Compounds with substituents at position 3 of the benzothiazole core were up to two orders of magnitude more effective than compounds with substituents at the carboxamide nitrogen. In addition, the 6-oxalylamino compounds were more potent inhibitors of E. coli DNA gyrase than the corresponding 6-acetamido analogues.
Topics: Topoisomerase II Inhibitors; DNA Gyrase; Binding Sites; Escherichia coli; Structure-Activity Relationship; Benzothiazoles; Adenosine Triphosphate; Molecular Structure; Quantum Theory; Anti-Bacterial Agents; Models, Molecular
PubMed: 38906068
DOI: 10.1016/j.bmc.2024.117798 -
ACS Infectious Diseases Jun 2024Globally, there have been increasing reports of antimicrobial resistance in nontyphoidal (NTS), which can develop into severe and potentially life-threatening diarrhea....
Globally, there have been increasing reports of antimicrobial resistance in nontyphoidal (NTS), which can develop into severe and potentially life-threatening diarrhea. This study focuses on the synergistic effects of DNA gyrase mutations and plasmid-mediated quinolone resistance (PMQR) genes, specifically , on fluoroquinolone (FQ) resistance in Typhimurium. By utilizing recombinant mutants, GyrA and GyrA, and QnrB19's, we discovered a significant increase in fluoroquinolones resistance when QnrB19 is present. Specifically, ciprofloxacin and moxifloxacin's inhibitory concentrations rose 10- and 8-fold, respectively. QnrB19 was found to enhance the resistance capacity of mutant DNA gyrases, leading to high-level FQ resistance. Additionally, we observed that the ratio of QnrB19 to DNA gyrase played a critical role in determining whether QnrB19 could protect DNA gyrase against FQ inhibition. Our findings underscore the critical need to understand these resistance mechanisms, as their coexistence enables bacteria to withstand therapeutic FQ levels, posing a significant challenge to treatment efficacy.
PubMed: 38898378
DOI: 10.1021/acsinfecdis.4c00150 -
Nature Chemistry Jun 2024Bacteria have evolved resistance to nearly all known antibacterials, emphasizing the need to identify antibiotics that operate via novel mechanisms. Here we report a...
Bacteria have evolved resistance to nearly all known antibacterials, emphasizing the need to identify antibiotics that operate via novel mechanisms. Here we report a class of allosteric inhibitors of DNA gyrase with antibacterial activity against fluoroquinolone-resistant clinical isolates of Escherichia coli. Screening of a small-molecule library revealed an initial isoquinoline sulfonamide hit, which was optimized via medicinal chemistry efforts to afford the more potent antibacterial LEI-800. Target identification studies, including whole-genome sequencing of in vitro selected mutants with resistance to isoquinoline sulfonamides, unanimously pointed to the DNA gyrase complex, an essential bacterial topoisomerase and an established antibacterial target. Using single-particle cryogenic electron microscopy, we determined the structure of the gyrase-LEI-800-DNA complex. The compound occupies an allosteric, hydrophobic pocket in the GyrA subunit and has a mode of action that is distinct from the clinically used fluoroquinolones or any other gyrase inhibitor reported to date. LEI-800 provides a chemotype suitable for development to counter the increasingly widespread bacterial resistance to fluoroquinolones.
PubMed: 38898213
DOI: 10.1038/s41557-024-01516-x -
BMC Veterinary Research Jun 2024The health of calves has a significant impact on the production of cows and livestock. Some desert plants have pharmacological importance, as they can be used to reduce...
The health of calves has a significant impact on the production of cows and livestock. Some desert plants have pharmacological importance, as they can be used to reduce antibiotic resistance. Our hypothesis is designed to detect Virulent- Multidrug-Resistant and Extended- spectrum Beta- lactamase Enterobacteriaceae (Virulent-MDR-ESBL Enterobacteriaceae and to determine whether Moringa oleifera has antibacterial activity against the detected isolates. A total of 39 Enterobacteriaceae isolates from 28 diarrheic samples were collected from calves aged between 20 days and 20 months from 3 different flocks in North Sinai, Sahl-Eltina region, Egypt. E.coli 46% (18/39), O157 13% (5/39), Klebsiella pneumoniae 41% (16/39). MDR members accounted for 87%, while ESBL isolates accounted for 43%. The antibacterial activity is represented by microdilution. Minimum inhibition concentration (MIC) for the methanol extract of Moringa oleifera ranged from 2.5,5,10, and 25mg/ ml among E.coli isolates, and O157 was susceptible to (2.5mg/ ml), Klebsiella pneumoniae isolates were susceptible to (5-50mg/ ml). Analysis of the methanol extract revealed that ferulic acid was the dominant phenolic compound with a concentration of 29,832 parts per million (ppm). In silico docking study expected the active site of ferulic acid to act on the tyrosine bacterial enzyme through Pi-alkyl, Pi-anion, Carbon hydrogen bonds, and extra ionic attractive interactions with copper ions which can stabilize ferulic acid inside the targeted pocket Diverse virulent gene profiles were observed in E. coli. The Shiga toxin-producing Escherichia coli (STEC) was reported in 83% of the isolated E. coli, while the DNA gyrase (gyrA) was harbored in 100% of Klebsiella pneumoniae isolates. Various profiles of antibiotic resistance genes for both E. coli and Klebsiella pneumoniae isolates were distinguished. bla genes were detected in 99% of E. coli and 100% of Klebsiella pneumoniae. Sequence analysis for E. coli strain DRC-North Sinai-Eg was placed in accession numbers (OP955786) for the Shiga toxin 2 gene (Stx2A), (OP997748) and (OP997749) for the Adhesion to host cell gene (Eae). For the hemolysine gene (hylA), the accession number was (OP946183). Klebsiella pneumoniae strain DRC-North Sinai-Eg was placed in (OP946180) for (gyrA). This study has proven the broad range of Moringa oliefera's antibacterial effects in vitro against the virulent-MDR- ESBL E. coli and Klebsiella pneumoniae isolated from North Sinai calves diarrhea. These are congruent with the disability effect on bacterial tyrosinase enzyme through docking study therefore, we recommend the usage of this desert plant as a prospective feed additive, we endorse this as an antibacterial new insight natural source and for the medication of considered pathogens with zoonotic impacts.
Topics: Animals; Cattle; Klebsiella pneumoniae; Moringa oleifera; Diarrhea; Cattle Diseases; Escherichia coli; Microbial Sensitivity Tests; Anti-Bacterial Agents; Plant Extracts; Drug Resistance, Multiple, Bacterial; beta-Lactamases; Egypt; Escherichia coli Infections; Klebsiella Infections; Virulence; Molecular Docking Simulation
PubMed: 38877453
DOI: 10.1186/s12917-024-04088-7 -
Zeitschrift Fur Naturforschung. C,... Jun 2024is a traditional medicinal plant used to treat hypertension, diarrhea and urinary disorders. Silica gel chromatographic separation of CHCl/MeOH (1:1) roots extract of...
is a traditional medicinal plant used to treat hypertension, diarrhea and urinary disorders. Silica gel chromatographic separation of CHCl/MeOH (1:1) roots extract of afforded seven compounds namely; β-sitosterol (), stigmasterol (), 6a, 12a-dehydro-deguelin (), tephrosin (), maackiain (), obovatin () and 6-oxo, 6a, 12a-dehydro-deguelin (). GC-MS analysis of essential oils from the root of displayed a total of 17 compounds of which cis-nerolidol (41.7 %) and cadinol (19.7 %) were the major constituents. CHCl/MeOH (1:1) extract, MeOH extract, maackiain () and obovatin () showed moderate inhibitory activity against with MIC value of 0.5, 0.66, 0.83 and 0.83 mg/mL, respectively, compared to ciprofloxacin (MIC of 0.078 μg/mL). 6a, 12a-dihydro-deguelin (), and 6-oxo, 6a, 12a-dehydro-deguelin () displayed significant activity against with MIC values of 0.66 mg/mL. Tephrosin () and maackiain () also showed moderate antibacterial activity against and with MIC values of 0.83 and 0.5 mg/mL, respectively, compared to ciprofloxacin (0.312 μg/mL). The radical scavenging activity results indicated that tephrosin (), obovatin () and 6-oxo, 6a, 12a-dehydro-deguelin () showed potent DPPH scavenging activity with IC values of 10.97, 10.43 and 10.73 μg/mL, respectively, compared to ascorbic acid (IC of 5.83 μg/mL). The docking prediction results revealed that 6a, 12a-dehydro-deguelin () displayed the best binding energy of -8.1 kcal/mol towards pyruvate kinase of (PDB ID: 3T07) and -7.9 kcal/mol towards urease (PDB ID: 1E9Y) and DNA gyrase B of (PDB: 4F86) receptors compared to ciprofloxacin (-7.2 to -8.0 kcal/mol). Maackiain () and obovatin () displayed the minimum binding energy of -7.9 and -8.2 kcal/mol towards the LasR protein of (PDB: ID 2UV) and FtsZ (PDB: ID 4M8I), respectively. The SwissADME drug-likeness and Pro Tox II toxicity prediction results indicated that compounds (-) obeyed Lipinski's rule of five with 0 violations and none of them were found to be hepatotoxic, mutagenic, and cytotoxic, respectively. The assessment results supported by the in silico analysis revealed that crude extracts and isolated compounds showed promising antibacterial and antioxidant activity, which proves the therapeutic potential of the roots of .
PubMed: 38865441
DOI: 10.1515/znc-2024-0044