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Pharmaceuticals (Basel, Switzerland) Sep 2023The spectrum of biological properties of s-triazine derivatives is broad and includes anti-microbial, anti-cancer, and anti-neurodegenerative activities, among others....
s-Triazine Derivatives Functionalized with Alkylating 2-Chloroethylamine Fragments as Promising Antimicrobial Agents: Inhibition of Bacterial DNA Gyrases, Molecular Docking Studies, and Antibacterial and Antifungal Activity.
The spectrum of biological properties of s-triazine derivatives is broad and includes anti-microbial, anti-cancer, and anti-neurodegenerative activities, among others. The s-triazine molecule, due to the possibility of substituting three substituents, offers many opportunities to obtain hybrid compounds with a wide variety of activities. A group of 1,3,5 triazine derivatives containing a dipeptide, 2-ethylpiperazine, and a methoxy group as substituents was screened for their antimicrobial activity. An in vitro study was conducted on pathogenic bacteria (, , and ), yeasts (), and filamentous fungi (, , , and ) via microdilution in broth, and the results were compared with antibacterial (Streptomycin) and antifungal (Ketoconazole and Nystatin) antibiotics. Several s-triazine analogues have minimal inhibitory concentrations lower than the standard. To confirm the inhibitory potential of the most active compounds against gyrases and , a bacterial gyrases inhibition assay, and molecular docking studies were performed. The most active s-triazine derivatives contained the -NH-Trp(Boc)-AlaOMe, -NH-Asp(OtBu)-AlaOMe, and -NH-PheOMe moieties in their structures.
PubMed: 37765056
DOI: 10.3390/ph16091248 -
Pathogens (Basel, Switzerland) Sep 2023It is widely accepted that favorable fitness in commensal colonization is one of the prime facilitators of clonal dissemination in bacteria. The question arises as to...
It is widely accepted that favorable fitness in commensal colonization is one of the prime facilitators of clonal dissemination in bacteria. The question arises as to what kind of fitness advantage may be wielded by uropathogenic strains of the two predominant fluoroquinolone- and multidrug-resistant clonal groups of -ST131-H30 and ST1193, which has permitted their unprecedented pandemic-like global expansion in the last few decades. The colonization-associated genes' content, carriage of low-cost plasmids, and integrons with weak promoters could certainly contribute to the fitness of the pandemic groups, although those genetic factors are common among other clonal groups as well. Also, ST131-H30 and ST1193 strains harbor fluoroquinolone-resistance conferring mutations targeting serine residues in DNA gyrase (GyrA-S83) and topoisomerase IV (ParC-S80) that, in those clonal backgrounds, might result in a commensal fitness benefit, i.e., beyond the antibiotic resistance per se. This fitness gain might have contributed not only to the widespread dissemination of these major clones in the healthcare setting but also to their long-term colonization of healthy individuals and, thus, circulation in the community, even in a low or no fluoroquinolone use environment. This evolutionary shift affecting commensal , initiated by mutations co-favorable in both antibiotics-treated patients and healthy individuals warrants more in-depth studies to monitor further changes in the epidemiological situation and develop effective measures to reduce the antibiotic resistance spread.
PubMed: 37764958
DOI: 10.3390/pathogens12091150 -
RSC Advances Sep 2023In this research, a fixed concentration (3 wt%) of Ag/PAA and PAA/Ag doped graphene quantum dots (GQDs) were synthesized using the co-precipitation technique. A variety...
In this research, a fixed concentration (3 wt%) of Ag/PAA and PAA/Ag doped graphene quantum dots (GQDs) were synthesized using the co-precipitation technique. A variety of characterization techniques were employed to synthesize samples to investigate their optical, morphological, structural, and compositional analyses, antimicrobial efficacy, and dye degradation potential with molecular docking analysis. GQDs have high solubility, narrow band gaps, and are suitable for electron acceptors and donors but show less adsorption and catalytic behavior. Incorporating polyacrylic acid (PAA) into GQDs increases the catalytic and antibacterial activities due to the carboxylic group (-COOH). Furthermore, introducing silver (Ag) increased the degradation of dye and microbes as it had a high surface-to-volume ratio. In addition, molecular docking studies were used to decipher the mechanism underlying the bactericidal action of silver and polyacrylic acid-doped graphene quantum dots and revealed inhibition of β-lactamase and DNA gyrase.
PubMed: 37746345
DOI: 10.1039/d3ra04741e -
Frontiers in Chemistry 2023Nanobiotechnology is a popular branch of science that is gaining interest among scientists and researchers as it allows for the green manufacturing of nanoparticles by...
Nanobiotechnology is a popular branch of science that is gaining interest among scientists and researchers as it allows for the green manufacturing of nanoparticles by employing plants as reducing agents. This method is safe, cheap, reproducible, and eco-friendly. In this study, the therapeutic property of fruit was mixed with the antibacterial activity of metallic copper to produce copper nanoparticles. The synthesis of copper nanoparticles was indicated by a color change from brown to blue. Physical characterization of copper nanoparticles (PN-CuNPs) was performed using UV-vis spectroscopy, FT-IR, SEM, EDX, XRD, and Zeta analyzer. PN-CuNPs exhibited potential antioxidant, antibacterial, and cytotoxic activities. PN-CuNPs have shown concentration-dependent, enhanced free radical scavenging activity, reaching maximum values of 92%, 90%, and 86% with DPPH, HO, and PMA tests, respectively. The antibacterial zone of inhibition of PN-CuNPs was the highest against (23 mm) and the lowest against (10 mm). PN-CuNPs showed 80% cytotoxicity against MCF-7 breast cancer cell lines. Furthermore, more than 50 components of extract were selected and subjected to molecular docking using the C-Docker protocol in the binding pockets of glutathione reductase, DNA gyrase topoisomerase II, and epidermal growth factor receptor (EGFR) tyrosine to discover their druggability. Pipercyclobutanamide A (26), pipernigramide F (32), and pipernigramide G (33) scored the highest Gibbs free energy at 50.489, 51.9306, and 58.615 kcal/mol, respectively. The ADMET/TOPKAT analysis confirmed the favorable pharmacokinetics, pharmacodynamics, and toxicity profiles of the three promising compounds. The present analysis helps us to understand the possible mechanisms behind the antioxidant, antibacterial, and cytotoxic activities of CuNPs and recommends them as implicit inhibitors of selected proteins.
PubMed: 37736256
DOI: 10.3389/fchem.2023.1218588 -
MSphere Oct 2023is one of the most common bacterial sexually transmitted infections. The emergence of antimicrobial-resistant is an urgent public health threat. Currently, the...
is one of the most common bacterial sexually transmitted infections. The emergence of antimicrobial-resistant is an urgent public health threat. Currently, the diagnosis of infection requires expensive laboratory infrastructure, while antimicrobial susceptibility determination requires bacterial culture, both of which are infeasible in low-resource areas where the prevalence of infection is highest. Recent advances in molecular diagnostics, such as pecific igh-sensitivity nzymatic eporter uning (SHERLOCK) using CRISPR-Cas13a and isothermal amplification, have the potential to provide low-cost detection of pathogen and antimicrobial resistance. We designed and optimized RNA guides and primer sets for SHERLOCK assays capable of detecting via the A gene and of predicting ciprofloxacin susceptibility via a single mutation in the gyrase A (A) gene. We evaluated their performance using both synthetic DNA and purified isolates. For A we created both a fluorescence-based assay and lateral flow assay using a biotinylated fluorescein reporter. Both methods demonstrated sensitive detection of 14 . isolates and no cross-reactivity with 3 non-gonococcal isolates. For A, we created a fluorescence-based assay that correctly distinguished between 20 purified isolates with phenotypic ciprofloxacin resistance and 3 with phenotypic susceptibility. We confirmed the A genotype predictions from the fluorescence-based assay with DNA sequencing, which showed 100% concordance for the isolates studied. We report the development of Cas13a-based SHERLOCK assays that detect and differentiate ciprofloxacin-resistant isolates from ciprofloxacin-susceptible isolates. IMPORTANCE the cause of gonorrhea, disproportionately affects resource-limited settings. Such areas, however, lack the technical capabilities for diagnosing the infection. The consequences of poor or absent diagnostics include increased disease morbidity, which, for gonorrhea, includes an increased risk for HIV infection, infertility, and neonatal blindness, as well as an overuse of antibiotics that contributes to the emergence of antibiotic resistance. We used a novel CRISPR-based technology to develop a rapid test that does not require laboratory infrastructure for both diagnosing gonorrhea and predicting whether ciprofloxacin can be used in its treatment, a one-time oral pill. With further development, that diagnostic test may be of use in low-resource settings.
Topics: Infant, Newborn; Humans; Neisseria gonorrhoeae; Gonorrhea; HIV Infections; Drug Resistance, Bacterial; Microbial Sensitivity Tests; Anti-Bacterial Agents; Ciprofloxacin
PubMed: 37732792
DOI: 10.1128/msphere.00416-23 -
Antimicrobial Agents and Chemotherapy Oct 2023Antimicrobial resistance has made a sizeable impact on public health and continues to threaten the effectiveness of antibacterial therapies. Novel bacterial...
Antimicrobial resistance has made a sizeable impact on public health and continues to threaten the effectiveness of antibacterial therapies. Novel bacterial topoisomerase inhibitors (NBTIs) are a promising class of antibacterial agents with a unique binding mode and distinct pharmacology that enables them to evade existing resistance mechanisms. The clinical development of NBTIs has been plagued by several issues, including cardiovascular safety. Herein, we report a sub-series of tricyclic NBTIs bearing an amide linkage that displays promising antibacterial activity, potent dual-target inhibition of DNA gyrase and topoisomerase IV (TopoIV), as well as improved cardiovascular safety and metabolic profiles. These amide NBTIs induced both single- and double-strand breaks in pBR322 DNA mediated by DNA gyrase, in contrast to prototypical NBTIs that cause only single-strand breaks. Unexpectedly, amides and targeted human topoisomerase IIα (TOP2α) causing both single- and double-strand breaks in pBR322 DNA, and induced DNA strand breaks in intact human leukemia K562 cells. In addition, anticancer drug-resistant K/VP.5 cells containing decreased levels of TOP2α were cross-resistant to amides and . Together, these results demonstrate broad spectrum antibacterial properties of selected tricyclic NBTIs, desirable safety profiles, an unusual ability to induce DNA double-stranded breaks, and activity against human TOP2α. Future work will be directed toward optimization and development of tricyclic NBTIs with potent and selective activity against bacteria. Finally, the current results may provide an additional avenue for development of selective anticancer agents.
Topics: Humans; Topoisomerase Inhibitors; DNA Gyrase; DNA Topoisomerase IV; Anti-Bacterial Agents; Staphylococcus aureus; DNA; Amides; Topoisomerase II Inhibitors; Microbial Sensitivity Tests
PubMed: 37724886
DOI: 10.1128/aac.00482-23 -
International Journal of... 2023Fluoroquinolones (FQs) have substantial activity against the Mycobacterium tuberculosis complex (MTBc) by preventing bacterial DNA synthesis through DNA gyrase...
BACKGROUND
Fluoroquinolones (FQs) have substantial activity against the Mycobacterium tuberculosis complex (MTBc) by preventing bacterial DNA synthesis through DNA gyrase inhibition. The reference standard for FQ-resistance testing is phenotypic drug-susceptibility testing (pDST) based on growth inhibition of MTBc in drug-containing Mycobacteria Growth Indicator Tube system (MGIT) media at a critical concentration (CC) that differentiates phenotypically wild-type from nonwild-type MTBc and at a clinical breakpoint that identifies strains that will likely still respond to treatment at higher doses. Despite the recent introduction of powerful new TB drugs, highly sensitive detection of clinically defined FQ resistance remains key.
METHOD
In this study, we re-evaluated the current WHO-recommended CCs of Lfx (1.0 mg/ml), Mfx (0.25 mg/ml), Gfx (0.25 μg/ml), and the nowadays, obsolete CC of Ofx (2.0 mg/ml) for MGIT, using 147 MTBc isolates with known gyrA and gyrB sequences including both high-and low-level FQ resistance-conferring mutants. We tested a wide range of drug concentrations covering the current and former/obsolete WHO-recommended CCs for FQs and some intermediate concentrations to challenge the current WHO-recommended CCs.
RESULTS
The specificity of all four CCs was 100%. The sensitivities varied: 92.4% for Ofx and Lfx, 85.7% for Mfx, and 83.2% for Gfx. Lowering the CC of Mfx to 0.125 mg/ml would allow to correctly classify all wild-type and mutant isolates while lowering the CC of Gfx to 0.125 mg/ml would still misclassify some gyrA/gyrB mutants as susceptible.
CONCLUSION
Based on our findings, a minimal inhibitory concentration of 0.125 mg/ml on MGIT medium is a more appropriate CC for Mfx and probably also as a surrogate for overall FQ resistance in the MTBc.
Topics: Humans; Fluoroquinolones; Mycobacterium tuberculosis; DNA Gyrase; Microbial Sensitivity Tests; Antitubercular Agents; Mutation; Drug Resistance, Bacterial
PubMed: 37721239
DOI: 10.4103/ijmy.ijmy_144_23 -
International Journal of... 2023Fluoroquinolone (FQ) antibiotics are among the most potent second-line antitubercular drugs these days. The aim of the study was to analyze the frequency and pattern of...
BACKGROUND
Fluoroquinolone (FQ) antibiotics are among the most potent second-line antitubercular drugs these days. The aim of the study was to analyze the frequency and pattern of genetic mutation in preextensive (pre-XDR) and extensively drug-resistant Mycobacterium tuberculosis using second-line line probe assay (LPA) and to compare drug-resistant mutations with different treatment outcomes.
METHODS
Sputum, lymph node aspirate, and cold accesses from patients with rifampicin-resistant Tuberculosis (TB) were subjected to first-line and second-line LPA (Genotype MTBDRsl by Hain Life Science, Germany) to assess additional drug resistance to fluoroquinolones (levofloxacin and moxifloxacin). Final treatment outcomes as per the National TB Elimination Program were assessed and compared with the mutation profile.
RESULTS
One hundred and fifty subjects were observed to have mutations associated with resistance to FQs and constituted the final study population. The most frequent mutation observed among GyrA drug resistance mutation was D94G (Gyr A MUT3C, 44/150, 66%) corresponding to high-level resistance to levofloxacin and moxifloxacin. The same mutation was associated with poor treatment outcome as died or treatment failure (odds ratio 2.50, relative risk 1.67, P = 0.043). The most common hetero-resistance mutation pattern observed in GyrA gene was wild type plus Asp94Gly mutation in 24.6% of isolates.
CONCLUSIONS
GyrA MUT3C hybridization corresponding to single-point mutation of aspartic acid to glycine at codon 94 constitutes the most common mutation in GyrA gene locus in M. tuberculosis with significant association with treatment outcome as died compared to those with treatment outcome as cured.
Topics: Humans; Mycobacterium tuberculosis; Fluoroquinolones; Levofloxacin; Moxifloxacin; Microbial Sensitivity Tests; Antitubercular Agents; Tuberculosis, Multidrug-Resistant; Mutation; Treatment Outcome; DNA Gyrase
PubMed: 37721235
DOI: 10.4103/ijmy.ijmy_116_23 -
Turkish Journal of Chemistry 2023The 2-substituted benzoxazole derivatives are known to exhibit a wide spectrum of biological potential. Two series of novel benzoxazole derivatives containing 2-phenyl...
The 2-substituted benzoxazole derivatives are known to exhibit a wide spectrum of biological potential. Two series of novel benzoxazole derivatives containing 2-phenyl and 2-N-phenyl groups were synthesized, by following the green chemistry approach. All the newly synthesized derivatives were screened against gram-positive bacteria (, ), gram-negative bacteria (, and the fungus (. Most of these compounds have demonstrated potent antibacterial activities, especially against at 25 μg/mL, along with moderate antifungal activity. Among these, two compounds, 21 and 18, showed interesting antibacterial profile. Molecular docking studies suggested that the antibacterial activity can be linked to the inhibition of . Overall, the study proposes that these biologically potent compounds can be considered for developing the next generation antimicrobial agents.
PubMed: 37720857
DOI: 10.55730/1300-0527.3535 -
ACS Omega Sep 2023Excessive use of antimicrobial medications including antibiotics has led to the emerging menace of antimicrobial resistance, which, as per the World Health Organization...
Excessive use of antimicrobial medications including antibiotics has led to the emerging menace of antimicrobial resistance, which, as per the World Health Organization (WHO), is among the top ten public health threats facing humanity, globally. This necessitates that innovative technologies be sought that can aid in the elimination of pathogens and hamper the spread of infections. Zinc oxide (ZnO) has multifunctionality owing to its extraordinary physico-chemical properties and functionality in a range of applications. In this research, ZnO nanoparticles (NPs) were synthesized from zinc nitrate hexahydrate, by a green synthesis approach using extract followed by characterization of the NPs. The obtained X-ray diffraction peaks of ZnO NPs matched with the standard JCPDS card (no. 89-510). The particles had a size of 20-24 nm, a wurtzite structure with a high crystallinity, and hexagonal rod-like shape. UV-Vis spectroscopy revealed absorption peaks between 369 and 374 nm of ZnO NPs synthesized from extract confirming the formation of ZnO. Fourier transform infrared confirmed the ZnO NPs as strong absorption bands were observed in the range of 381-403 cm corresponding to Zn-O bond stretching. Negative values of the highest occupied molecular orbital-lowest unoccupied molecular orbital for ZnO NPs indicated the good potential to form a stable ligand-protein complex. Docking results indicated favorable binding interaction between ZnO and DNA gyrase subunit b with a binding energy of -2.93 kcal/mol. ZnO NPs at various concentrations inhibited the growth of and . Minimum inhibitory concentration values of ZnO NPs against and were found to be 92.07 ± 0.13 and 88.13 ± 0.35 μg/mL, respectively, at a concentration of 2 mg/mL. AO/EB staining and fluorescence microscopy revealed the ability of ZnO NPs to kill and cells. Through the findings of this study, it has been shown that extract can be used in a green synthesis approach to generate ZnO NPs, which can be employed as alternatives to antibiotics and a tool to eliminate drug-resistant microbes in the future.
PubMed: 37692252
DOI: 10.1021/acsomega.3c03908