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Global Challenges (Hoboken, NJ) Dec 2023Various concentrations of samarium-grafted-carbon nitride (Sm-g-CN) doped-bismuth oxobromide (BiOBr) quantum dots (QDs) are prepared by the co-precipitation method....
Various concentrations of samarium-grafted-carbon nitride (Sm-g-CN) doped-bismuth oxobromide (BiOBr) quantum dots (QDs) are prepared by the co-precipitation method. Elemental evaluation, morphological, optical, and functional group assessment are studied employing characterization techniques. Based on the XRD pattern analysis, it is determined that BiOBr exhibits a tetragonal crystal structure. The electronic spectroscopy revealed an absorption peak for BiOBr at 315 nm and the bandgap energy ( ) decreasing from 3.9 to 3.8 eV with the insertion of Sm-g-CN. The presence of vibrational modes related to BiOBr at 550 cm is confirmed through FTIR spectra. TEM revealed that pure BiOBr possessed non-uniform QDS, and agglomeration increased with the addition of Sm-g-CN. The catalytic performance of Sm-g-CN into BiOBr (6 mL) in a neutral medium toward rhodamine B exhibited excellent results (99.66%). The bactericidal activity is evaluated against multi-drug resistance (MDR) once the surface area is increased by dopant and the measured inhibition zone is assessed to be 3.65 mm. Molecular docking results supported the in vitro bactericidal potential of Sm-g-CN and Sm-g-CN doped-BiOBr as DNA gyrase inhibitors. This study shows that the novel Sm-g-CN doped-BiOBr is a better catalyst that increases specific semiconductor's catalytic activity (CA).
PubMed: 38094862
DOI: 10.1002/gch2.202300118 -
ACS Omega Nov 2023This paper targets the nuclease activity of polymeric chemical compounds toward bacterial genomic DNA and also elucidates their probable drug-like properties against the...
This paper targets the nuclease activity of polymeric chemical compounds toward bacterial genomic DNA and also elucidates their probable drug-like properties against the enzymes bacterial gyrase complex and human topoisomerase. Poly--chloroaniline, poly--chloroaniline, and poly-,-chloroaniline were synthesized by a chemical oxidation method. The structure of the polymers was characterized by the powder X-ray diffraction pattern, which suggested the ordered structure of the polymer, where the parallel and perpendicular periodicities of the polymeric chain were arranged systematically. The molecular transition of polymers was determined by a UV-visible spectrum study. A polymeric arrangement of the molecule can be seen in scanning electron microscopy (SEM) images. Among the three polymers chosen for the biological study and molecular docking studies, poly--chloroaniline showed more affinity to bind against both the selected targets (HT IIIb TB and SAGS) in comparison to the ortho- and ortho-meta substituents of polyaniline. The biophysical interaction analysis is in line with molecular docking, which shows that poly--chloroaniline forms many different categories of interactions and binds very strongly with the selected targets. The synthesized and tested molecules have potential nuclease activity, which is well aligned with molecular docking studies against the bacterial gyrase complex and human topoisomerase.
PubMed: 38046322
DOI: 10.1021/acsomega.3c05970 -
PloS One 2023The emergence of antimicrobial resistance in commensal bacteria poses a serious public health burden worldwide. Commensals can disseminate the resistance genes to...
The emergence of antimicrobial resistance in commensal bacteria poses a serious public health burden worldwide. Commensals can disseminate the resistance genes to pathogenic bacteria causing life-threatening infections. This cross-sectional study was designed to investigate the antimicrobial resistance pattern and molecular mechanism(s) of ciprofloxacin resistance in commensal E. coli from three major one health components (humans, animals and the environment) in Bangladesh. Samples were randomly collected from broiler chickens, broiler farm environments and hospitalized human patients from the same geographical area. Isolation and identification of E. coli were performed following standard bacteriological techniques. Antimicrobial susceptibility testing (AST) was performed by disk diffusion and broth microdilution methods. Mutation at the quinolone-resistance determining region (QRDR) was analyzed by sequencing. Of 450 samples, a total of 287 (63.8%; 95% CI 59.2-68.1%) E. coli strains was isolated, where 240 (83.6%; 95% CI 78.9-87.5%) strains were phenotypically resistant to ciprofloxacin. The prevalence of ciprofloxacin-resistant E. coli in broiler chicken, broiler farm environments and hospitalized human patients are 77.6%, 88.8% and 89% respectively. In AST against nine antimicrobials, all the isolates were found to be multidrug-resistant (MDR). The minimum inhibitory concentration (MIC) of ciprofloxacin was ranged from 4 to >128mg/L. Point mutations were detected in several sites of QRDR, specifically at 83 and 87 amino acid positions in gyrA gene, and 56, 57, 78, 80 and 84 amino acid positions in parC gene. Mutations resulted in amino acid substitutions. Phylogenetic analysis of gyrA and parC gene sequences showed a close relationship between the strains isolated from different sources. This study demonstrates a high prevalence of ciprofloxacin resistance in commensal E. coli in humans, animals and environment interface and their genealogically similarity poses an alarming public health consequence.
Topics: Humans; Animals; Ciprofloxacin; Escherichia coli; Chickens; Anti-Bacterial Agents; Prevalence; Phylogeny; Cross-Sectional Studies; One Health; DNA Gyrase; Anti-Infective Agents; Quinolones; Microbial Sensitivity Tests; Amino Acids; Drug Resistance, Bacterial
PubMed: 37983240
DOI: 10.1371/journal.pone.0294043 -
BMC Microbiology Nov 2023Endophytic fungi, particularly from higher plants have proven to be a rich source of antimicrobial secondary metabolites. The purpose of this study is to examine the...
Endophytic fungi, particularly from higher plants have proven to be a rich source of antimicrobial secondary metabolites. The purpose of this study is to examine the antimicrobial potential of three endophytic fungi Aspergillus sp. SA1, Aspergillus sp. SA2, and Aspergillus sp. SA3, cultivated from Nigella sativa seeds against Staphylococcus aureus (ATCC 9144), Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853), Klebsiella pneumoniae (ATCC 13883), MRSA (ATCC 33591), and human pathogen Candida albicans (ATCC 10231). Furthermore, the most active cultivated endophytic fungi were molecularly identified via internal transcribed spacer (ITS) sequencing. HR-ESIMS guided approach has been used successfully in chemical profiling of 26 known bioactive secondary metabolites (1-26), which belongs to different classes of natural compounds such as polyketides, benzenoids, quinones, alcohols, phenols or alkaloids. Finally, in-silico interactions within active site of fungal Cyp51 and bacterial DNA gyrase revealed possibility of being a hit-target for such metabolites as antimicrobials.
Topics: Humans; Endophytes; Nigella sativa; Microbial Sensitivity Tests; Anti-Infective Agents; Seeds; Fungi
PubMed: 37974074
DOI: 10.1186/s12866-023-03085-4 -
International Journal of Molecular... Oct 2023Topoisomerase I (TopoI) in , encoded by , is a suitable target for drug development. Seconeolitsine (SCN) is a new antibiotic that specifically blocks this enzyme. We...
Topoisomerase I (TopoI) in , encoded by , is a suitable target for drug development. Seconeolitsine (SCN) is a new antibiotic that specifically blocks this enzyme. We obtained the mutant, which encodes an enzyme less active than the wild type () and more resistant to SCN inhibition. Likely due to the essentiality of TopoI, we were unable to replace the allele by the mutant version. We compared the in vivo activity of TopoIRA and TopoIWT using regulated overexpression strains, whose genes were either under the control of a moderately (P) or a highly active promoter (P). Overproduction of TopoIRA impaired growth, increased SCN resistance and, in the presence of the gyrase inhibitor novobiocin (NOV), caused lower relaxation than TopoIWT. Differential transcriptomes were observed when the and expression levels were increased about 5-fold. However, higher increases (10-15 times), produced a similar transcriptome, affecting about 52% of the genome, and correlating with a high DNA relaxation level with most responsive genes locating in topological domains. These results confirmed that TopoI is indeed the target of SCN in and show the important role of TopoI in global transcription, supporting its suitability as an antibiotic target.
Topics: Transcriptome; DNA Topoisomerases, Type I; Streptococcus pneumoniae; DNA Gyrase; Anti-Bacterial Agents
PubMed: 37958782
DOI: 10.3390/ijms242115800 -
European Journal of Pharmaceutical... Jan 2024Antimicrobial resistance caused by the excessive and inappropriate use of antibacterial drugs is a global health concern. Currently, we are walking a fine line between... (Review)
Review
The overview of development of novel bacterial topoisomerase inhibitors effective against multidrug-resistant bacteria in an academic environment: From early hits to in vivo active antibacterials.
Antimicrobial resistance caused by the excessive and inappropriate use of antibacterial drugs is a global health concern. Currently, we are walking a fine line between the fact that most bacterial infections can still be cured with the antibiotics known so far, and the emergence of infections with bacteria resistant to several drugs at the same time, against which we no longer have an effective drug. Therefore, new antibacterial drugs are urgently needed to curb the hard-to-treat infections. Our group has developed new antibacterials from the class of novel bacterial topoisomerase inhibitors (NBTIs) that exhibit broad-spectrum antibacterial activity. This article reviews our efforts in developing highly potent NBTIs over the past decade. Following the discovery of an initial hit with potent enzyme inhibitory and broad-spectrum antibacterial activity, an extensive hit-to-lead campaign was conducted with the goal of optimizing physicochemical properties, reducing hERG inhibition, and maintaining antibacterial activity against both Gram-positive and Gram-negative bacteria, with a focus on methicillin-resistant Staphylococcus aureus (MRSA). This optimization strategy resulted in an amide-containing, focused NBTI library with compounds exhibiting potent antibacterial activity against Gram-positive bacteria, reduced hERG inhibition, no cardiotoxicity in in vivo zebrafish model, and favorable in vivo efficacy in a neutropenic murine thigh infection model for MRSA infections.
Topics: Mice; Animals; Topoisomerase Inhibitors; Anti-Bacterial Agents; Methicillin-Resistant Staphylococcus aureus; DNA Gyrase; Zebrafish; Gram-Positive Bacteria; Gram-Negative Bacteria; Microbial Sensitivity Tests; Topoisomerase II Inhibitors
PubMed: 37949194
DOI: 10.1016/j.ejps.2023.106632 -
The Journal of Biological Chemistry Dec 2023Macromolecular crowding, manifested by high concentrations of proteins and nucleic acids in living cells, significantly influences biological processes such as enzymatic...
Macromolecular crowding, manifested by high concentrations of proteins and nucleic acids in living cells, significantly influences biological processes such as enzymatic reactions. Studying these reactions in vitro, using agents such as polyetthylene glycols (PEGs) and polyvinyl alcohols (PVAs) to mimic intracellular crowding conditions, is essential due to the notable differences from enzyme behaviors observed in diluted aqueous solutions. In this article, we studied Mycobacterium tuberculosis (Mtb) DNA gyrase under macromolecular crowding conditions by incorporating PEGs and PVAs into the DNA supercoiling reactions. We discovered that high concentrations of potassium glutamate, glycine betaine, PEGs, and PVA substantially stimulated the DNA supercoiling activity of Mtb DNA gyrase. Steady-state kinetic studies showed that glycine betaine and PEG400 significantly reduced the K of Mtb DNA gyrase and simultaneously increased the V or k of Mtb DNA gyrase for ATP and the plasmid DNA molecule. Molecular dynamics simulation studies demonstrated that PEG molecules kept the ATP lid of DNA gyrase subunit B in a closed or semiclosed conformation, which prevented ATP molecules from leaving the ATP-binding pocket of DNA gyrase subunit B. The stimulation of the DNA supercoiling activity of Mtb DNA gyrase by these molecular crowding agents likely results from a decrease in water activity and an increase in excluded volume.
Topics: DNA Gyrase; Mycobacterium tuberculosis; Betaine; Kinetics; Adenosine Triphosphate; DNA; DNA, Superhelical
PubMed: 37944619
DOI: 10.1016/j.jbc.2023.105439 -
BioRxiv : the Preprint Server For... Oct 2023Fluoroquinolones (FQs) are potent antibiotics of clinical significance, known for their unique mechanism of action as gyrase poisons, which stabilize gyrase-DNA cleavage...
Fluoroquinolones (FQs) are potent antibiotics of clinical significance, known for their unique mechanism of action as gyrase poisons, which stabilize gyrase-DNA cleavage complexes and convert gyrase into a DNA-damaging machinery. Unfortunately, FQ resistance has emerged, and these antibiotics can cause severe side effects. Therefore, discovering novel gyrase poisons with different chemical scaffolds is essential. The challenge lies in efficiently identifying them from compound libraries containing thousands or millions of drug-like compounds, as high-throughput screening (HTS) assays are currently unavailable. Here we report a novel fluorescence-based, T5 exonuclease-amplified DNA cleavage assay for gyrase poison discovery. This assay capitalizes on recent findings showing that multiple gyrase molecules can simultaneously bind to a plasmid DNA molecule, forming multiple gyrase-DNA cleavage complexes on the same plasmid. These gyrase-DNA cleavage complexes, stabilized by a gyrase poison, can be captured using sarkosyl. Proteinase K digestion results in producing small DNA fragments. T5 exonuclease, selectively digesting linear and nicked DNA, can fully digest the fragmented linear DNA molecules and, thus, "amplify" the decrease in fluorescence signal of the DNA cleavage products after SYBR Green staining. This fluorescence-based, T5 exonuclease-amplified DNA cleavage HTS assay is validated using a 50-compound library, making it suitable for screening large compound libraries.
PubMed: 37904923
DOI: 10.1101/2023.10.16.562555 -
Microorganisms Oct 2023The emergence of multidrug-resistant pathogens creates public health challenges, prompting a continuous search for effective novel antimicrobials. This study aimed to...
The emergence of multidrug-resistant pathogens creates public health challenges, prompting a continuous search for effective novel antimicrobials. This study aimed to isolate marine actinomycetes from South Africa, evaluate their in vitro antimicrobial activity against and Shiga toxin-producing , and characterize their mechanisms of action. Marine actinomycetes were isolated and identified by 16S rRNA sequencing. Gas chromatography-mass spectrometry (GC-MS) was used to identify the chemical constituents of bioactive actinomycetes' secondary metabolites. Antibacterial activity of the secondary metabolites was assessed by the broth microdilution method, and their mode of actions were predicted using computational docking. While five strains showed antibacterial activity during primary screening, only strain SOD(B)ST2SA2 exhibited activity during secondary screening for antibacterial activity. GC-MS identified five major bioactive compounds: 1-octadecene, diethyl phthalate, pentadecanoic acid, 6-octadecenoic acid, and trifluoroacetoxy hexadecane. SOD(B)ST2SA2's extract demonstrated minimum inhibitory concentration and minimum bactericidal concentration, ranging from 0.78-25 mg/mL and 3.13 to > 25 mg/mL, respectively. Diethyl phthalate displayed the lowest bacterial protein-binding energies (kcal/mol): -7.2, dihydrofolate reductase; -6.0, DNA gyrase B; and -5.8, D-alanine:D-alanine ligase. Thus, marine SOD(B)ST2SA2 is a potentially good source of antibacterial compounds that can be used to control STEC and .
PubMed: 37894198
DOI: 10.3390/microorganisms11102539 -
Microorganisms Sep 2023This study focused on the assessment of the antimicrobial resistance of () and () isolated from bovine mastitis milk samples and the revealing anti-mastitis potential...
This study focused on the assessment of the antimicrobial resistance of () and () isolated from bovine mastitis milk samples and the revealing anti-mastitis potential of phytocompounds of and through molecular docking analysis. The mastitis milk samples were collected from various dairy farms for the isolation of the bacteria ( and ) and their response to antibiotics. Ethanolic extracts of both plants were prepared. Their antibacterial activity was evaluated, and they were processed for phytochemical analysis after which, molecular docking analysis with pathogenic proteins of the bacteria was carried out. Parametric and non-parametric statistical analyses were performed to reach the conclusions of this study. The findings of the study revealed a higher drug resistance (≥40%) of against ampicillin, amikacin, and vancomycin, while exhibited the highest resistance to ampicillin, erythromycin, and ciprofloxacin. The ethanolic extracts of the and plants produced a ZOI between 18 and 23 mm against multidrug-resistant and . Gas chromatography-mass spectrophotometry (GC-MS) was used to explore 15 phytocompounds from and 18 phytocompounds from . The molecular docking analysis of 2cyclopenten-1-one,3,4,4 trimethyl and Bis (2ethylhexyl) phthalate of showed a binding affinity of -4.8 kcal/mol and -5.3 kcal/mol and -5.9 kcal/mol and -7.1 kcal/mol against the DNA Gyrase and toxic shock syndrome toxin-1 proteins of and , respectively. The suberic acid monomethyl ester of showed a binding affinity of -5.9 kcal/mol and -5 kcal/mol against the outer membrane protein A and Topoisomerase IV protein of and -5.1 kcal/mol and -5.8 kcal/mol against the toxic shock syndrome toxin-1 and Enterotoxin B proteins of . Similarly, 2,2,4-trimethyl-1,3-pentanediol di-iso-butyrate showed a binding affinity of -6.5 kcal/mol and -5.3 kcal/mol against the outer membrane protein A and Topoisomerase IV of and -5.2 kcal/mol and -5.9 kcal/mol against the toxic shock syndrome toxin-1 and Enterotoxin B proteins of , respectively. The study concluded that there was an increasing trend for the antimicrobial resistance of and , while the and plant extracts expressed significant affinity to tackle this resistance; hence, this calls for the development of novel evidence-based therapeutics.
PubMed: 37894108
DOI: 10.3390/microorganisms11102450