MIC Values Research Articles

ANTIMICROBIAL ACTIVITY OF LINEAR CHALCOGEN-FUNCTIONALIZED DERIVATIVES OF THIAZOLO[2,3-b]QUINAZOLINIUM

The study examines the antimicrobial activity of linear chalcogen-functionalized derivatives in the thiazoloquinazoline series against the pathogen Staphylococcus aureus and investigates the influence of low-intensity laser radiation on the sensitivity of thiazolo[2,3-b]quinazoline chlorides. The research involved synthesizing the investigated thiazolo[2,3-b]quinazoline chlorides via chalcogen-induced cyclization. For the first time, 2,3-dihydro-2-((trichloro-λ4-selanyl)methyl)-5-oxo-8-(trifluoromethyl)-5H-thiazolo[2,3-b]quinazolin-10-ium chloride was obtained, and its structure was confirmed using advanced spectral methods (¹H NMR and IR spectroscopy). Based on experimental microbiological data, it was determined that 2,3-dihydro-2-((trichloro-λ4-tellanyl)methyl)-5-oxo-8-(trifluoromethyl)-5H-thiazolo[2,3-b]quinazolin-10-ium chloride showed lower minimum inhibitory and minimum bactericidal concentrations (62.5 mg/mL) compared to its selenium analog, with MIC and MBC values of 250 mg/mL. The nature of the chalcogen significantly affects the antimicrobial activity of the base thiazolo[2,3-b]quinazoline against Staphylococcus aureus. The application of low-intensity red-spectrum laser radiation does not enhance the activity of the quinazolines studied.

Antimicrobial activity and cytotoxic and epigenetic effects of tannic acid-loaded chitosan nanoparticles

Tannic acid (TA) is a potent antitumor agent, but its low bioavailability and absorption limit its use. In this study, it was loaded into chitosan-based nanoparticles (Chi-NPs) to overcome these limitations and to improve its antimicrobial and anticancer activities. TA-loaded Chi-NPs (Chi-TA-NPs) were synthesized using the ionic gelation method and physicochemically characterized by FE-SEM, FTIR, XRD, PDI, DLS, and zeta potential analysis. Additionally, the antimicrobial activity of Chi-TA-NPs against two G+ bacterial strains, two G− bacterial strains, and a fungal strain (Candida albicans) was investigated using the microbroth dilution method. MTT assay was used to examine the cytotoxic effects of Chi-TA-NPs on HepG2 cells. The expression of DNA methyltransferase 1 (DNMT1), DNMT3A, and DNMT3B was examined in HepG2 cells using RT-qPCR. The amount of 5-methylcytosine in the HepG2 cell-derived genomic DNA was measured using ELISA. FE-SEM micrographs showed the loading of TA into the chitosan-based formulation. The peaks detected in the XRD and FTIR analyses confirmed the formation of the Chi-TA-NPs. The PDI value (0.247 ± 0.03), size (567.0 ± 25.84 nm), and zeta potential (17.0 ± 5.86 mV) confirmed the relative stability of Chi-TA-NPs. A constant release profile in line with the Korsmeyer-Peppas model was detected for Chi-TA-NPs, such that approximately 44% of TA was released after 300 min. In addition, Chi-TA-NPs exhibited effective antimicrobial activity against the studied microbial strains, as manifested by MIC values ranging from 250 to 1000 µg/mL. Chi-TA-NPs induced cytotoxicity in liver tumor cell line, with an IC50 value of 500 µg/mL. Furthermore, Chi-TA-NPs considerably decreased the expression of DNMT1 (2.52-fold; p = 0.01), DNMT3A (2.96-fold; p = 0.004), and DNMT3B (2.94-fold; p < 0.0001). However, 5-methylcytosine levels in HepG2 cells were unaffected by Chi-TA-NPs treatment (p = 0.62). Finally, the antimicrobial, cytotoxic, and epigenetic effects of Chi-TA-NPs were more pronounced than those of free TA and the unloaded Chi-NPs. In conclusion, Chi-TA-NPs exhibit promising potential for reducing microbial growth and promoting cytotoxicity in liver cancer cells.

Exploring the Bioactive Potential of Pinus mugo Turra Essential Oil: Volatile Composition, Antioxidant, Antimicrobial, Antibiofilm and Insecticidal Activities

ABSTRACTPinus represents a potential source of valuable bioactive substances. In this study, the chemical composition and biological activity of essential oils extracted from Pinus mugo Turra needles (PMEO) were investigated. GC/MS analyses were used to assess the volatile elements found in the PMEO sample. The antioxidant activity was evaluated using DPPH and ABTS techniques. Antimicrobial properties were evaluated against yeasts and bacteria (both Gram‐positive and Gram‐negative) using the disc diffusion method, minimal inhibition concentration and vapour phase on fruit and vegetable models. Mass spectrometry and the crystal violet technique were used to measure the antibiofilm activity. The contact application method was used to assess the insecticidal activity of different concentration of PMEO against Harmonia axyridis. The GC/MS analysis identified β‐phellandrene (20.5%), α‐pinene (19.4%), δ‐3‐carene (16.7%), β‐pinene (11.1%) and β‐myrcene (9.4%) as main constituents. PMEO exhibited antioxidant activity against DPPH and ABTS radical species, with IC50 values of 1.92 and 1.14 mg/mL, respectively. PMEO showed an inhibitory effect against microbial strains ranging from 6.67 to 13.33 mm. By employing the microdilution method, PMEO showed antimicrobial activity with MIC50 values ranging from 2.52 to 7.41 mg/mL and MIC90 values ranging from 2.72 to 7.7 mg/mL. The in situ antimicrobial investigations revealed that PMEO exerts the highest activity against E. aerogenes and P. putida on apple and beetroot models. Furthermore, PMEO exhibited noteworthy potential against biofilm‐forming S. enterica growing on plastic and glass surfaces. Additionally, an evaluation of the PMEO insecticidal potential was performed using H. axyridis. Insecticidal properties against H. axyridis were observed at concentrations of 50% and 100%. PMEO displayed good antioxidant, antibacterial and insecticidal properties, significant antibiofilm features and excellent preservative properties for extending the shelf life of foods.

Assessing Syzygium aromaticum: From Chemical Profiling to Antioxidant, Antistaphylococcal, and Biocompatibility Attributes.

Staphylococcal infections challenge current treatments due to adverse effects and drug resistance, prompting the exploration of plant-derived compounds for their promising properties. This study aimed to analyze Syzygium aromaticum essential oil, aqueousand ethyl acetate extracts for antioxidant and antistaphylococcal effects against sensitive and resistant clinical isolates. Erythrocytes were used as model cells for biocompatibility. The SA-EO was extracted via hydrodistillation and compounds were identified using GC-MS. The antioxidant activity was assessed using various tests, while antimicrobial activity was evaluated through disk diffusion and microdilution assays. Results showed Eugenol as the major compound in SA-EO. The AE exhibited high phenolic and flavonoid content. SA-EO demonstrated antioxidant activity with IC50 values of 84.63 ± 1.94 µg/mL (TAC) and 52.88 ± 1.44 µg/mL (FRAP). The AE-SA showed scavenging effects with EC50 values of 266.52 ± 50.62 µg/mL (DPPH) and 140.67 ± 44.36 μg/mL (NO). The antistaphylococcal activity revealed significant sensitivity of SA-EO with MIC and MBC values ranging from 0.316 to 1.266 mg/mL. SA-EO showed low hemolytic activity even at high concentrations. Overall, these findings highlight the potential of Syzygium aromaticum in combating multidrug-resistant bacteria and underscore its role as a source of bioactive compounds with antioxidant properties.

Prevalence of Mobile Colistin Resistance (&lt;i&gt;mcr&lt;/i&gt;) Genes in &lt;i&gt;Acinetobacter baumannii&lt;/i&gt;: Isolates of Clinical Infection from an Iranian University Hospital

Background: The emergence of colistin resistance is a global issue that threatens the effectiveness of colistin treatment against multidrug-resistant Gram-negative bacteria. Objectives: The present study reports on the prevalence of colistin resistance and mcr-encoding genes in Acinetobacter baumannii strains isolated from patients referred to Shahid Rahimi Hospital, Khorramabad, Iran, from January to August 2019. Methods: A total of 47 non-duplicate A. baumannii isolates were obtained from clinical specimens of patients. Colistin susceptibility of the isolates was assessed using the broth microdilution method, and the presence of mcr-encoding genes was determined through the use of PCR. Results: Out of the total 47 isolates belonging to A. baumannii, 14 isolates (29.8%) were resistant to colistin. The minimum inhibitory concentration (MIC) of colistin ranged from 2 to 256 μg/mL, and the MIC50 and MIC90 values for colistin were 0.25 μg/mL and 16 μg/mL, respectively. The presence of mcr-1 and mcr-2 was detected in 6 (12.7%) and 2 (4%) isolates, respectively. However, no isolates harbored the mcr-3 gene. Except for one isolate, none of the mcr-positive isolates exhibited phenotypic resistance to colistin. Conclusions: The higher phenotypic prevalence of colistin resistance compared to genotypic characterization, along with the discrepancy with the presence of mcr genes, suggests the need to monitor and consider all molecular mechanisms of colistin resistance as a last-resort treatment option.

Nature-inspired Novel Quaternary Ammonium Compounds: Synthesis, Antibacterial and Antibiofilm Activity.

Inspired by marine compounds isolated from sponges and the increased need for new effective antimicrobials, novel quaternary ammonium compounds with long alkyl chains (C8-C12) were designed and synthesized. Antibacterial and antibiofilm activity of new compounds was evaluated against six microbial strains (S. aureus, E. coli, and P. aeruginosa). All synthesized ammonium salts displayed antibacterial activity with MIC values ranging from 5.0 to 25.0 μg/mL. In addition, most compounds showed strong inhibition of biofilm formation of S. aureus ATCC 25923, P. aeruginosa PA01, and colistin-resistant P. aeruginosa (CRPA) at a concentration of 5.0 μg/mL. Ammonium salt 3 showed 100 % inhibitory activity against all tested bacterial biofilms except that of colistin-resistant S. aureus (CRSA).

Synthesis, characterization, quantum chemical modelling, molecular docking, in silico and in vitro assessment of 3-(2-bromo-5-fluorophenyl))-1-(thiophen-2-yl)prop-2-en-1-one

α,β-unsaturated carbonyl compounds have extensive applications in various fields, such as organic, inorganic, analytical, and biological. In the modern era, they offer excellent pharmacological application prospects and find widespread use in the pharmaceutical industry. The current study revealed the synthesis and characterization of a novel 3-(2-bromo-5-fluorophenyl)-1-(thiophen-2-yl) prop-2-en-1-one (CY3). In vitro their antimicrobial (Pseudomonas aeruginosa, Klebsiella pneumonia, Escherichia coli, Staphylococcus aureus, and Acinetobacter baumannii), antifungal ( Candida parapsilosis, Candida tropicalis, and Candida albicans), cytotoxicity (VERO and Hep-G2 cells), in silico, and molecular docking analysis were also performed. The in-silico analysis evaluated the drug-likeness properties of the compound CY3 using various filtering rules, including Lipinski’s, Ghose filter, Veber, Egan, Muegge, and Medicinal Chemistry alerts such as Pan Assay Interference Structures (PAINS), Brenk, and Lead-likeness. Then, molecular docking studies performed using the AutoDock (AD4), Vina, and iGEMDOCK tools to determine the mechanism by which the CY3 compound interact with the bacterial strains. Here, five different receptors were selected, such as DNA gyrase, glucose 6-phosphate synthase (GlmS), dihydrofolate reductase (DHFR), dehydrosqualene synthase (DHSS), and undecaprenyl pyrophosphate synthase (UDPPS), for molecular docking analysis. The CY3 compound showed a good binding affinity with the two target proteins, DHFR and DHSS, respectively, with maximum binding energies of about − 7.07 and − 7.05 kcal/mol. The synthesized CY3 compound exhibited moderate antibacterial activity with a MIC value > 100 µg/mL against all five bacterial strains and moderate antifungal activity with a MIC value > 50 µg/mL against all three fungal strains. Drug-likeness analyses also support their favourable bioavailability.

Self-assembled sustainable bionanocomposite hydrogels from chitosan for the combination chemotherapy of hydrophobic and hydrophilic drugs.

Self-assembled hydrogels derived from naturally sourced polymers have gained significant interest in drug delivery applications, owing to their potential, exceptional biocompatibility and sustainable properties. This work presents the development and application of self-assembled nanocomposite hydrogels from chitosan and nanosilver as a pH responsive drug delivery system for the controlled release of doxorubicin and paclitaxel in anticancer therapy. Chitosan was functionalized with 4-formyl benzoic acid for incorporating both hydrophobic and hydrophilic anticancer drugs. The self-assembled nanocomposite hydrogels formed from chitosan and 4-formyl benzoic acid by various non-covalent interactions were studied by FT-IR, Dynamic Light Scattering (DLS), and rheology analysis. Rheology studies demonstrated the hydrogel's shear-thinning nature, enabling easy injection. The antibacterial activity can be evidenced by agar-well diffusion assay and MIC values were measured. The antibacterial effect was analyzed by agar-well diffusion assays and H2-DCFDA assay, providing a comprehensive understanding. In-vivo pharmacokinetic studies on Wistar rats demonstrated promising and effective systemic circulation of drug loaded material in blood, thus supporting its potential for therapeutic applications. All these studies and results demonstrates feasibility and a novel synergistic dual drug delivery approach, promising the synergy between hydrophobic paclitaxel (PTX) and hydrophilic Doxorubicin hydrochloride (Dox.HCl), for improved anticancer efficacy.

Genomic analysis of IMP-8-producing Enterobacter hormaechei with a novel plasmid pK432-IMP

Carbapenem-resistant Enterobacter cloacae (CR-ECC) complex has posed significant challenges to the clinical treatment of infections, and Enterobacter hormaechei is the most commonly identified nosocomial pathogen of CR-ECC. Carbapenemases were detected by the immunocolloidal gold technique. The MIC values were determined by VITEK2. The genome sequence of strain K432 was obtained and analyzed. We isolated the IMP-8-producing E. hormaechei strain K432 from a patient's urine specimen in a Chinese Hospital, which exhibited resistance to multiple antibiotics including ceftazidime, piperacillin/tazobactam, aztreonam, imipenem, meropenem, ciprofloxacin, levofloxacin, minocycline and trimethoprim/sulfamethoxazole. The genome of strain K432 was composed of the chromosome cK432 (4,863 kb) and three plasmids: pK432-IMP (45.8 kb), pK432-TEM (75.6 kb) and pK432-NR (4.8 kb). In K432, six drug-resistant genes were detected, including blaACT-7 and fosA on cK432, blaIMP-8 and qnrS1 on pK432-IMP, blaSFO-1 and blaTEM-1 on pK432-TEM. pK432-IMP belonged to a novel incompatibility group, and pK432-TEM was an IncR plasmid. Both of these two plasmids shared similar conserved backbone regions with their reference plasmids, respectively. However, the single accessory regions in these two plasmids were different from their reference plasmids, indicating that new recombination and integration events had occurred in K432. This study provides a comprehensive understanding of the genomic characterization of K432 and identified a novel plasmid for IMP transmission. Further investigation and surveillance are warranted for pK432-IMP-type plasmid. While routine monitoring of MDR E. hormaechei strains is necessary in China.

Synthesis, single crystal investigations, DFT studies, biological activities, DNA cytotoxicity and molecular docking studies of copper(II) complex derived from the new o-vanillin Schiff base ligand

A novel Schiff base derivative, (E)-N’-(2-hydroxy-3-methoxybenzylidene)-2-phenylacetohydrazide (HMPH, H2L), and its Cu(II) complex were synthesized through the direct condensation of o-vanillin with phenylacetichydrazide in ethanol under reflux conditions. The synthesized ligand was identified usingelemental analysis, Fourier transform infrared (FTIR) and ultraviolet–visible (UV–Vis.) spectroscopy. The structures of HMPH (C16H16N2O3)2 and its Cu(II) complex [Cu(L)(H2O)]·H2O (C16H16N2CuO4·H2O) were analysed by single crystal X-ray diffraction technique. The X-ray diffraction results showed that HMPH crystallised in an orthorhombic Pca21 space group with a Z value of 8, while [Cu(L)(H2O)]·H2O crystallised in a monoclinic C 2/c space group with the same z value. The Cu(II) ion is coordinated to the acetohydrazide ligands via hydrazone nitrogen, aceto oxygen (N(2) and O(1)) and hydroxyl O(2) atoms. In addition to the single crystal structures of HMPH and [Cu(L)(H2O)]·H2O, the optimised molecular structures, molecular electrostatic potential meps, molecular orbital energy values, and interactions between DNA bases and molecular structures are determined by DFT/B3LYP/6-311G(d, p) for HMPH and DFT/B3LYP/LanL2DZ for [Cu(L)(H2O)]·H2O. The copper complex was found to be more potent than the organic ligand in terms of antimicrobial activity, with a strong anti-biofilm effect even at low MIC values. The cytotoxicity of the synthesized compounds was investigated on MDA-MB-231 cell lines. The [Cu(L)(H2O)]·H2O complex was found to be more lethal than the HMPH ligand. Furthermore, molecular docking studies of HMPH and [Cu(L)(H2O)]·H2O with P. aeruginosa ATCC27853 (PDB ID: 6P8U) were presented to explain the observed antibacterial activity and the mechanism-of-action.

Discovery of structurally diverse sesquiterpenoids from Streptomyces fulvorobeus isolated from Elephas maximus feces and their antifungal activities

Thirty-six structurally diverse sesquiterpenoids, including caryolanes (1–12), germacranes (13–16), isodaucane (17), cadinanes (18–22), epicubenols (23, 24), oplopanane (25), pallenanes (26, 27), and eudesmanes (28–36), were isolated from the fermentation broth of Streptomyces fulvorobeus derived from Elephas maximus feces. Pallenane is a kind of rarely reported sesquiterpene with a distinctive C5/C3 bicyclic skeleton and was firstly found from microbial source. The structures of fifteen new compounds (1–4, 13–15, 17, 18, 22, 23, 25–28) were established through detailed spectroscopic data analysis, which included data from experimental and calculated ECD spectra as well as Mosher’s reagent derivative method. Compound 34 exhibited moderate antifungal activity against Cryptococcus neoformans and Cryptococcus gattii with MIC values of 50 μg/mL. It effectively inhibited biofilm formation and destroyed the preformed biofilm, as well as hindered the adhesion of Cryptococcus species. The current work would enrich the chemical diversity of sesquiterpenoid family.Graphical

PKPD modelling and simulation of longitudinal meropenem in vivo effects against Escherichia coli and Klebsiella pneumoniae strains with high MIC

BackgroundCarbapenem-resistant bacteria pose a threat to public health. Characterizing the pharmacokinetics-pharmacodynamics (PKPD) of meropenem longitudinally in vivo against resistant bacteria could provide valuable information for development and translation of carbapenem-based therapies. ObjectivesTo assess the time course of meropenem effects in vivo against strains with high MIC to predict PK/PD indices and expected efficacy in patients using a modelling approach. MethodsA PKPD model was built on longitudinal bacterial count data to describe meropenem effects against six Escherichia coli and Klebsiella pneumoniae strains (MIC values 32-128 mg/L) in a 24h mouse thigh infection model. The model was used to derive PK/PD indices from simulated studies in mice and to predict the efficacy of different infusion durations with high-dose meropenem (2 g q8h/q12h for normal/reduced kidney function) in patients. ResultsData from 592 mice were available for model development. The estimated meropenem concentration-dependent killing rate was not associated with differences in MIC. The fraction of time that unbound concentrations exceeded EC50 (fT>EC50, EC50=1.01 mg/L) showed higher correlations than fT>MIC. For all investigated strains, bacteriostasis at 24h was predicted for prolonged infusions of high-dose meropenem monotherapy in >90% of patients. ConclusionsThe developed PKPD model successfully described bacterial growth and meropenem killing over time in the thigh infection model. For the investigated strains the MIC, determined in vitro, or MIC-based PK/PD indices, did not predict in vivo response. Simulations suggested prolonged infusions of high-dose meropenem to be efficacious in patients infected by the studied strains.

Antiphytopathogenic Diphenyl Ethers from the Marine-derived Fungus Aspergillus sydowii

Background: Natural products from the marine-derived Aspergillus sp. have great potential in agricultural usage due to their broad biological activities. Objective: This study was designed to investigate the antiphytopathogenic compounds from marinederived fungus Aspergillus sydowii LW09. Methods: The compounds were isolated and purified by chromatography methods, and their structures were elucidated by analysis of the NMR and MS spectroscopic data as well as comparison with those of literature. All compounds were evaluated for antibacterial activities against phytopathogenic bacteria Pseudomonas syringae and Ralstonia solanacarum, along with spore germination inhibition of phytopathogenic fungi Fusarium oxysporum and Alternaria alternata. Results: Two diphenyl ethers violaceols I (1) and II (2), along with two alkaloids acremolin (3) and WIN 64821 (4) were isolated from the fermentation extracts of A. sydowii LW09. Compound 1 showed significant antibacterial activity against P. syringae and R. solanacarum with the same MIC values of 4 μg/mL, while compound 2 showed obvious antibacterial activity against P. syringae and R. solanacarum with MIC values of 2 and 1 μg/mL, respectively. Moreover, both 1 and 2 could inhibit the spore germination of F. oxysporum in the concentration range of 64–128 μg/mL. In addition, violaceol I (1) also inhibited the spore germination of A. alternata at 128 μg/mL. Conclusion: This study provided the potential antiphytopathogenic drug candidate for further studies.

Novel Triazolo[4,3-a]pyrazines as Potential MmpL3 Inhibitors: Design, Synthesis, Antitubercular Evaluation and Molecular Docking Studies

A series of biologically active novel triazolo[4,3-a]pyrazines (5a-f) were synthesized and characterized by spectroscopic techniques. The synthesized compounds 5a-f were evaluated for their in vitro anti-tubercular (anti-TB) activity against drug-sensitive Mtb H37Rv (ATCC 27294) strain as well as two drug-resistant Mtb strains viz. Mtb H37Rv ATCC 35822 (INH-resistant) and Mtb H37Rv ATCC 35837 (ETH-resistant). The synthesized compounds 5a-f displayed good to moderate anti-TB activity against drug-sensitive, INH-resistant and ETH-resistant Mtb H37Rv strains. Among all the compounds tested, compound 5c was found to be significantly potent. It inhibited the growth of drug-sensitive, INH-resistant and ETH-resistant Mtb H37Rv strains with MIC values 0.59 ± 0.11 µM, 20.83 ± 0.67 µM and 15.37 ± 0.14 µM, respectively. Moreover, compounds 5a-f were also tested for their cytotoxic efficacy against the mammalian Vero cell line at a maximum concentration of 50 µM. Molecular docking experiments of compounds 5a-f with the mycobacterial membrane protein large 3 (MmpL3) were performed to justify the biological activity and provide insight into the possible mechanism of action and binding mode of compounds. In silico predictions were used to validate compound toxicity descriptors, drug scores and drug-likeness properties.

Synthesis, characterization, DNA, BSA, antimicrobial, antioxidant and molecular docking studies of gadolinium(III) based complexes

The present study reports the synthesis of two new gadolinium-metal-based complexes with mixed ligands, [Gd(L1)2(py)(H2O)3] (C1) and [Gd (L2)2(phen)(H2O)2] (C2), where L1 represents 3-(4 cyanophenyl) acrylate and L2 as 3-(4 fluorophenyl) acrylate. The complexes were characterized by various analytical techniques including FT-IR, PXRD, TGA, DSC, SEM and EDX to determine structural elucidation, binding mode, crystallinity, thermal stability, morphology and elemental composition, respectively. The synthesized complexes were tested for DNA (salmon sperm) and BSA interaction studies to infer their antitumor potential. The binding constants obtained for C1 and C2 with SS DNA were 3.03 × 104 and 3.2 × 104 while with BSA observed as 1.59 × 105 and 1.22 × 105, respectively. In vitro antimicrobial potential of both complexes was determined against various bacterial and fungal strains. Experimental results showed complex C2 is more active than C1 against all selected bacterial strains and showed higher antibacterial potential against E. coli with a zone of inhibition (ZOI) of 35 mm. The antibacterial potential of C2 was further investigated by calculating the MIC (IC50) value. MIC of complex C2 was assessed using visual inspection (turbidity) and spectrophotometric assay at 600 nm. The findings of the spectrophotometric approach have greater sensitivity than the standard disc diffusion assays. The molecular docking studies were conducted to validate further and compare the findings of experimental results which exhibited that complex C2 has an excellent binding capacity with the target protein (5CDQ) with free binding energy −12.23 kcal/mol. Antioxidant potentials of the complexes were assessed using phosphomolybdenum assay, which demonstrated that complex C2 exhibits higher antioxidant activity than complex C1.

Design, Synthesis and Biological Evaluation of 4,6-Substituted 2-Styrylquinoline Derivatives: Potential Antimicrobial and Anticancer Agents

A series of novel 4,6-substituted 2-styrylquinoline derivatives (3a-h) was designed and synthesized based on the substitution in quinoline scaffolds (with Br, H, NO2 at C6 position) as well as the substitution in the styryl moeity (at C4' position). The target compounds were investigated for their antimicrobial activity against Gram-positive Staphylococcus aureus (ATCC 25923), Enterococcus faecalis (ATCC 29212) and Gram-negative bacterium Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27853) and Candida albicans (ATCC 10231) and anticancer activity against human colon adenocarcinoma HT29 cells. Compared to standard drug ciprofloxacin, compounds 3e, 3b and 3c showed significant antibacterial activity against Staphylococcus aureus, Enterococcus faecalis and Escherichia coli. Additionally, synthesized compound 3e had significant activity against Candida albicans with MIC value of 8 µg/mL. In anticancer study, the maximum cell death rate was found in compounds 3e, 3b and 3c at the dose of 100 µM i.e., 72.9%., 44.01% and 35.46%, respectively and the measured IC50 were 58.84, 114.53 and 130 µM. The cytotoxic potential of compound 3e was confirmed by AO-EtBr dual staining assay in which red fluorescence of necrotic cells lost their membrane integrity due to toxicity induced by compound 3e. This growth inhibition and apoptotic activity of compound 3e was dose-dependent when the colour changed from green to red. Furthermore, in silico studies were conducted on the synthesized compounds to elucidate the potential mechanisms of action against dihydrofolate reductase (DHFR) from E. coli, DNA gyrase from P. aeruginosa, DHFR from S. aureus, acetolactate synthase from K. pneumoniae and DHFR from C. albicans. The derivatives also exhibited the strongest ligand-receptor binding affinity. Additionally, ADME analysis was performed to predict the pharmacokinetic profiles of the compounds, indicating good oral drug-like properties.

Investigation of clonal relationship in hospital-associated Candida parapsilosis isolates.

We aimed to investigate the clonal relationship and antifungal susceptibility of C. parapsilosis isolated from hospitalized patients and to determine whether it is due to transmission or not and the spread status of resistant isolates. Between January 2017 and June 2019, totally 277 C parapsilosis isolated from blood, urine and catheter samples of adult or pediatric in-patient (intensive care and service) who applied to Mycology laboratory in our hospital were included in the study. All isolates were identified using conventional methods, API 20C AUX (Biomerieux, France) semi-automated system and confirmed by MALDI-TOF MS Biotyper Smart (Bruker Daltonik GmbH, Germany). Randomly amplified polymorphic DNA (RAPD) PCR method was used for molecular genotyping of isolates. MIC values for fluconazole, anidulafungin and amphotericin B were determined according to the M27-A3 CLSI broth microdilution reference method guideline. Seven different band patterns (A-G) were detected in 277 isolates by RAPD PCR method. According to the rank order of the isolates, 170 (61.37%) C, 65 (23.47%) A, 18 (6.50%) G, 11 (3.97%) B, six (2.17%) E, two (0.72%) F and one (0.36%) D patterns were determined. When the band patterns of the isolates were evaluated according to the years, it was detected that C pattern continued between 2017 and 2019 and that all isolates continued to spread only as C pattern in 2019. While 211 (76.17%) of the isolates were resistant to fluconazole (≥ 8µg/ml), two (0.72%) were resistant to amphotericin B (≥ 2µg/ml) and two (0.72%) were intermediate to anidulafungin. It is noteworthy that the spread of the C pattern in C. parapsilosis strains has increased over the years and is the main pattern isolated from the whole hospital. The detection of high fluconazole resistance in C. parapsilosis isolates in our hospital may also be related to the dominant pattern.

Effect of mutation of secG gene in drug resistance and physiological and biochemical activities of Xanthomonas oryzae pv. oryzae.

Bacterial leaf blight caused by the bacterium Xanthomonas oryzae pv. oryzae has a substantial effect on the yield of rice crops. The secretory (Sec) pathway, essential for efflux transport in bacteria, remains insufficiently studied in X. oryzae pv. oryzae, especially regarding its roles in drug resistance and physiology. This study involved transcriptome analysis on two X. oryzae pv. oryzae strains: a secG deletion strain (∆secG) and its complemented strain (C: ∆secG). In comparison to the parental strain PXO99A, ∆secG exhibited slower growth, with reductions in swimming (20.67%) and swarming (12.59%), while maintaining 76.7% of its biofilm formation capacity and 63.6% of exopolysaccharide production. The minimum inhibitory concentration (MIC50) values for an n-butanol extract of Bacillus velezensis HN-2 (HN-2E) and bacitracin against ∆secG were 0.426 μg/mL (5.3% lower than that of PXO99A) and 10.905 μg/mL, respectively. Notably, ∆secG exhibited increased susceptibility to hydrogen peroxide (H2O2), being inhibited at 0.25 mm compared to 0.3 mm for PXO99A and C: ∆secG. In the presence of 0.2 mM H2O2, the susceptibility of ∆secG to HN-2E increased by 31.22% (MIC50 = 0.159 μg/mL), while PXO99A and C: ∆secG exhibited MIC50 values of 0.280 and 0.291 μg/mL, respectively. Our findings demonstrate that Bacillus-induced H2O2 production enhances the sensitivity of X. oryzae pv. oryzae to biocontrol agents, providing valuable insights for the prevention of bacterial leaf blight. These results highlight the significance of the Sec pathway in the behavior and resistance of X. oryzae pv. oryzae, as well as potential areas for further research on plant diseases. © 2024 Society of Chemical Industry.

Decarboxylation of the Catalytic Lysine Residue by the C5α-Methyl-Substituted Carbapenem NA-1-157 Leads to Potent Inhibition of the OXA-58 Carbapenemase.

Antibiotic resistance in bacteria is a major global health concern. The wide spread of carbapenemases, bacterial enzymes that degrade the last-resort carbapenem antibiotics, is responsible for multidrug resistance in bacterial pathogens and has further significantly exacerbated this problem. Acinetobacter baumannii is one of the leading nosocomial pathogens due to the acquisition and wide dissemination of carbapenem-hydrolyzing class D β-lactamases, which have dramatically diminished available therapeutic options. Thus, new antibiotics that are active against multidrug-resistantA. baumannii and carbapenemase inhibitors are urgently needed. Here we report characterization of the interaction of the C5α-methyl-substituted carbapenem NA-1-157 with one of the clinically important class D carbapenemases, OXA-58. Antibiotic susceptibility testing shows that the compound is more potent than commercial carbapenems against OXA-58-producingA. baumannii, with a clinically sensitive MIC value of 1 μg/mL. Kinetic studies demonstrate that NA-1-157 is a very poor substrate of the enzyme due mainly to a significantly reduced deacylation rate. Mass spectrometry analysis shows that inhibition of OXA-58 by NA-1-157 proceeds through both the classical acyl-enzyme intermediate and a reversible covalent species. Time-resolved X-ray crystallographic studies reveal that upon acylation of the enzyme, the compound causes progressive decarboxylation of the catalytic lysine residue, thus severely impairing deacylation. Overall, this study demonstrates that the carbapenem NA-1-157 is highly resistant to degradation by the OXA-58 carbapenemase.

Antibiotic susceptibility situation of environmental Legionella pneumophila isolates in Southern Germany

ABSTRACT Antimicrobial resistance is an emerging problem in hospitals and long-term healthcare facilities. Early detection of susceptibility pattern changes in pathogenic bacteria can prevent treatment failures. Therefore, this study chose to investigate the antibiotic susceptibility situation of Legionella pneumophila isolates from hospitals and long-term healthcare facilities in Southern Germany. Serogroups and minimal inhibitory concentrations (MICs) of nine antibiotics were determined from 41 L. pneumophila strains. In total, 28% of the collected strains belonged to the more pathogenic serogroup 1, whereas 72% belonged to serogroups 2–14. Among the tested antibiotics, rifampicin had the lowest MIC90 value. The MIC90 values can be summarized in the following order: rifampicin &amp;lt; levofloxacin &amp;lt; moxifloxacin &amp;lt; ciprofloxacin &amp;lt; clarithromycin &amp;lt; azithromycin &amp;lt; erythromycin &amp;lt; doxycycline &amp;lt; tigecycline.