A Mini-Review of In Vitro Data for Candida Species, Including C. auris, Isolated during Clinical Trials of Three New Antifungals: Fosmanogepix, Ibrexafungerp, and Rezafungin.

This mini-review summarizes the clinical outcomes and antifungal susceptibility results, where available, for three new antifungals, including fosmanogepix, ibrexafungerp, and rezafungin, against Candida isolates cultured from patients in clinical trials. When reported, most of the data were generated by the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method or by both the CLSI and European Committee on Antimicrobial Susceptibility Testing (EUCAST) methodologies. For fosmanogepix, we summarize the in vitro data for C. auris isolates from 9 patients and for Candida spp. cultured from 20 patients in two clinical trials. Ibrexafungerp has also been evaluated in several clinical trials. From conference proceedings, a total of 176 Candida isolates were evaluated in the FURI and CARES studies, including 18 C. auris isolates (CARES study). However, MIC data are not available for all clinical isolates. Results from the ReSTORE rezafungin phase 3 clinical study also included in vitro results against Candida spp., but no patients with C. auris infections were included. In conclusion, this mini-review summarizes insights regarding clinical outcomes and the in vitro activity of three new antifungals against Candida spp. cultured from patients in clinical trials.

Biological Activity and Phytochemical Characteristics of Star Anise (Illicium verum) Essential Oil and Its Anti-Salmonella Activity on Sous Vide Pumpkin Model.

Illicium verum, commonly known as star anise, represents one of the notable botanical species and is recognized for its rich reservoir of diverse bioactive compounds. Beyond its culinary application as a spice, this plant has been extensively utilized in traditional medicine. Given the contemporary emphasis on incorporating natural resources into food production, particularly essential oils, to enhance sensory attributes and extend shelf life, our study seeks to elucidate the chemical composition and evaluate the antibacterial (in vitro, in situ) and insecticidal properties of Illicium verum essential oil (IVEO). Also, microbiological analyses of pumpkin sous vide treated with IVEO after inoculation of Salmonella enterica were evaluated after 1 and 7 days of study. GC/MS analysis revealed a significantly high amount of (E)-anethole (88.4%) in the investigated EO. The disc diffusion method shows that the antibacterial activity of the IVEO ranged from 5.33 (Streptococcus constellatus) to 10.33 mm (Citrobacter freundii). The lowest minimal inhibition concentration was found against E. coli and the minimum biofilm inhibition concertation was found against S. enterica. In the vapor phase, the best antimicrobial activity was found against E. coli in the pears model and against S. sonei in the beetroot model. The application of the sous vide method in combination with IVEO application decreased the number of microbial counts and eliminated the growth of S. enterica. The most isolated microbiota identified from the sous vide pumpkin were Bacillus amyloliquefaciens, B. cereus, B. licheniformis, and Ralstonia picketii. Modifications to the protein composition of biofilm-forming bacteria S. enterica were suggested by the MALDI TOF MS instigations. The IVEO showed insecticidal potential against Harmonia axyridis. Thanks to the properties of IVEO, our results suggest it can be used in the food industry as a natural supplement to extend the shelf life of foods and as a natural insecticide.

Discovery of novel pyridone-benzamide derivatives possessing a 1-methyl-2-benzimidazolinone moiety as potent EZH2 inhibitors for the treatment of B-cell lymphomas.

Enhancer of zeste homolog 2 (EZH2) is a promising therapeutic target for diffuse large B-cell lymphoma. In this study, based on the binding model of 1 (tazemetostat) with polycomb repressive complex 2 (PRC2), we designed and synthesized a series of tazemetostat analogs bearing a 1-methyl-2-benzimidazolinone moiety to improve the inhibitory activity of EZH2 wild-type (WT) and Y641 mutants and enhance metabolic stability. After the assessment of the structure-activity relationship at enzymatic and cellular levels, compound N40 was identified. Biochemical assays showed that compound N40 (IC50 = 0.32 nM) exhibited superior inhibitory activity against EZH2 WT, compared with 1 (IC50 = 1.20 nM), and high potency against EZH2 Y641 mutants (EZH2 Y641F, IC50 = 0.03 nM; EZH2 Y641N, IC50 = 0.08 nM), which were approximately 10-fold more active than those of 1 (EZH2 Y641F, IC50 = 0.37 nM; EZH2 Y641N, IC50 = 0.85 nM). Furthermore, compound N40 (IC50 = 3.52 ±â€¯1.23 nM) effectively inhibited the proliferation of Karpas-422 cells and was more potent than 1 (IC50 = 35.01 ±â€¯1.28 nM). Further cellular experiments showed that N40 arrested Karpas-422 cells in the G1 phase and induced apoptosis in a dose-dependent manner. Moreover, N40 inhibited the trimethylation of lysine 27 on histone H3 (H3K27Me3) in Karpas-422 cells bearing the EZH2 Y641N mutant. Additionally, N40 (T1/2 = 177.69 min) showed improved metabolic stability in human liver microsomes compared with 1 (T1/2 = 7.97 min). Our findings suggest N40 as a promising EZH2 inhibitor; further investigation remains warranted to confirm our findings and further develop N40.

In vitro activity of tedizolid against 43 species of Nocardia species.

The purpose of the present study was to evaluate the in vitro activity of tedizolid against several clinically significant species of Nocardia by comparing with that of linezolid. A total of 286 isolates of Nocardia species, including 236 clinical isolates recovered from patients in Japan and 50 strains (43 species) purchased from NITE Biological Resource Center, were studied. Antimicrobial susceptibility testing was performed using the broth microdilution method. For the 286 Nocardia isolates, the minimal inhibitory concentration (MIC)50 and MIC90 values of tedizolid were 0.25 and 0.5 µg/ml, and those of linezolid were 2 and 2 µg/ml, respectively. The distribution of the linezolid/tedizolid ratios (MICs of linezolid/MICs of tedizolid) showed that tedizolid had four- to eight-fold higher activity than linezolid in 96.1% (275/286) of Nocardia isolates. Both the tedizolid and linezolid MIC90 values for Nocardia brasiliensis were two-fold higher than those for the other Nocardia species. Both tedizolid and linezolid had low MIC values, 0.25-1 µg/ml and 0.5-4 µg/ml, respectively, even against nine isolates (five species) that were resistant to trimethoprim/sulfamethoxazole. One Nocardia sputorum isolate showed reduced susceptibility to tedizolid (4 µg/ml). Bioinformatics analysis suggests different resistance mechanisms than the oxazolidinone resistance seen in enterococci and staphylococci.

Supercritical Fluid Extraction of Bioactive Components from Apple Peels and Their Modulation of Complex I Activity in Isolated Mitochondria.

Supercritical fluid extraction (SFE) was used to extract bioactive compounds from apple (Malus domestica) peel waste from three different Italian cultivars. The bioactive fractions were extracted applying a temperature of 60 °C and a pressure of 250 bar for 15 min with 20% ethanol as co-solvent, at a flow rate of 2 mL/min. The total polyphenol (TP), anthocyanin (TA), ascorbic acid (AA), and antioxidant activity contents (TACs) were measured, while chromatographic analyses were performed to highlight the differences between the extracts. The Stark cultivar had the highest levels of polyphenols, anthocyanins, and ascorbic acid, while the Royal Gala cultivar showed the highest total antioxidant activity. SFE extracts were then tested for their effect on the mitochondrial NADH-ubiquinone oxidoreductase (Complex I) activity on mitochondria isolated from human embryonic kidney cells (HEK239). The Stark extract showed the most positive response in terms of NADH oxidation. The results obtained in this work highlight the potential of apple peel waste as a source of functional phytocompounds and suggest that Stark cultivar extracts may be exploited for pharmacological applications. This study supports the circular bioeconomy by promoting the use of waste products as a valuable resource.

In Vitro Antibacterial Activity of Ceftobiprole and Comparator Compounds against Nation-Wide Bloodstream Isolates and Different Sequence Types of MRSA.

Bloodstream infections by bacteria, especially multidrug-resistant bacteria, remain a worldwide public health concern. We evaluated the antibacterial activity of ceftobiprole and comparable drugs against different bloodstream isolates and different sequence types of methicillin-resistant Staphylococcus aureus (MRSA) in China. We found that MRSA, methicillin-susceptible Staphylococcus aureus (MSSA), and methicillin-susceptible coagulase-negative Staphylococcus (MSCNS) displayed ceftobiprole sensitivity rates of >95%, which are similar to the rates for linezolid, daptomycin, and vancomycin. Of the tested MRCNS strains, 90.4% were sensitive to ceftobiprole. The sensitivities of ST59, ST398, and ST22 MRSA to ceftobiprole were higher than that of ST239. Ceftobiprole's MIC50/90 value against Enterococcus faecalis was 0.25/2 mg/L, whereas Enterococcus faecium was completely resistant to this drug. Ceftobiprole exhibited no activity against ESBL-positive Enterobacterales, with resistance rates between 78.6% and 100%. For ESBL-negative Enterobacterales, excluding Klebsiella oxytoca, the sensitivity to ceftobiprole was comparable to that of ceftazidime, ceftriaxone, and cefepime. The MIC50/90 value of ceftobiprole against Pseudomonas aeruginosa was 2/16 mg/L, and for Acinetobacter baumannii, it was 32/>32 mg/L. Thus, ceftobiprole shows excellent antimicrobial activity against ESBL-negative Enterobacterales and Pseudomonas aeruginosa (comparable to that of ceftazidime, ceftriaxone, and cefepime); however, it is not effective against ESBL-positive Enterobacterales and Acinetobacter baumannii. These results provide important information to clinicians.

'Synthesis, antiviral activity, molecular docking, and molecular dynamics studies of ethoxy phthalimide pyrazole derivatives against Cytomegalovirus and Varicella-Zoster virus: potential consequences and strategies for developing new antiviral treatments'.

Substituted ethoxy phthalimide pyrazole derivatives (6a-e) have been produced using a one-pot synthesis technique. Spectral analysis was used to establish the molecular structure of the synthesized compounds, and they were examined in silico and in vitro for their ability to bind to and inhibit replication of the AD-169 strain, the Davis strain of CMV, the OKA strain and the 07/1 strain of Varicella-Zoster virus (VZV). Molecular Docking was used to estimate the binding mechanism and energy of compounds 4, 6a-e to their respective target proteins, thymidine kinase (TK), Varicella-Zoster protease (VZP) of VZV and tegument protein pp71 (TPpp71) of Cytomegalovirus (CMV). The MIC50 and EC50 were utilized to evaluate the antiviral and cytotoxic activities of test compounds in human embryonic lung (HEL) cells against the two reference medicines, Ganciclovir and Acyclovir. The chemicals studied showed a high affinity for binding sites and near binding sites of target proteins by generating H-bonds, carbon-hydrogen bonds, π-anion, π-sulfur, π-sigma, alkyl and π-alkyl interactions. All of the test compounds (6a-e) had higher binding energy than the standard medications. The ADME/T data suggests that these potential inhibitors are less toxic. Drug-protein complexes are structurally compact and demonstrate minimal conformational change in molecular dynamics (MDs) simulations, indicating stability and stiffness. MM-PBSA and post-simulation analysis can predict lead compound active cavity binding stability. By inhibiting multitargeted proteins, these synthetic compounds may improve antiviral therapy. Our research suggests that these unique synthesized chemicals may be useful and accessible adjuvant antiviral therapy for Varicella Zoster and CMV. HighlightsTwo components synthesis of substituted ethoxy phthalimide pyrazole derivatives (6a-e).Tested compounds (6a-e) have antiviral and cytotoxicity activity against CMV and Varicella-Zoster virus (VZV) in HEL cells.Compounds bind to TK, Varicella-Zoster protease (VZP) of VZV, and modeled TPpp71 of Cytomegalovirus (CMV).In comparison to reference drugs, compounds have strong binding free energy and interactions with VZV and CMV protein complexes.The RMSD, RMSF, Rg, residual correlative motion (RCM), No. of hydrogen bonds, protein secondary structure content, per-residue protein secondary structure and MM/PBSA energy calculated for the selected compound with thymidine kinase (TK), VZP of VZV, and modeled tegument protein pp71 (TPpp71) of CMV through MD simulation studies for 50 ns.In comparison to the two reference drugs, ligands/compounds were found to meet the Lipinski rule of five and to have strong biological activity.Communicated by Ramaswamy H. Sarma.

Role of Fisetin in Selected Malignant Neoplasms in Women.

A promising therapeutic window and cost-effectiveness are just two of the potential advantages of using naturally derived drugs. Fisetin (3,3',4',7-tetrahydroxyflavone) is a natural flavonoid of the flavonol group, commonly found in fruit and vegetables. In recent years, fisetin has gained wide attention across the scientific community because of its broad spectrum of pharmacological properties, including cytotoxic activity against most abundant cancers. By stimulating or inhibiting selected molecular targets or biochemical processes, fisetin could affect the reduction of metastasis or cancer progression, which indicates its chemotherapeutic or chemopreventive role. In this review, we have summarized the results of studies on the anticancer effects of fisetin on selected female malignancies, both in in vitro and in vivo tests, i.e., breast, cervical, and ovarian cancer, published over the past two decades. Until now, no article dedicated exclusively to the action of fisetin on female malignancies has appeared. This review also describes a growing number of nanodelivery systems designed to improve the bioavailability and solubility of this natural compound. The reported low toxicity and activity of fisetin on cancer cells indicate its valuable potential, but large-scale clinical trials are urgently needed to assess real chemotherapeutic efficacy of this flavonoid.

A US-based national surveillance study for the susceptibility and epidemiology of Clostridioides difficile isolates with special reference to ridinilazole: 2020-2021.

We have previously reported on the susceptibility and epidemiology of Clostridioides difficile isolates from six geographically dispersed medical centers in the United States. This current survey was conducted with isolates collected in 2020-2021 from six geographically dispersed medical centers in the United States, with specific attention to susceptibility to ridinilazole as well as nine comparators. C. difficile isolates or stools from patients with C. difficile antibiotic-associated diarrhea were collected and referred to a central laboratory. After species confirmation of 300 isolates at the central laboratory, antibiotic susceptibilities were determined by the agar dilution method [M11-A9, Clinical and Laboratory Standards Institute (CLSI)] against the 10 agents. Ribotyping was performed by PCR capillary gel electrophoresis on all isolates. Ridinilazole had a minimum inhibitory concentration (MIC) 90 of 0.25 mcg/mL, and no isolate had an MIC greater than 0.5 mcg/mL. In comparison, fidaxomicin had an MIC 90 of 0.5 mcg/mL. The vancomycin MIC 90 was 2 mcg/mL with a 0.7% resistance rate [both CLSI and European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria]. The metronidazole MIC 90 was 1 mcg/mL, with none resistant by CLSI criteria, and a 0.3% resistance rate by EUCAST criteria. Among the 50 different ribotypes isolated in the survey, the most common ribotype was 014-020 (14.0%) followed by 106 (10.3%), 027 (10%), 002 (8%), and 078-126 (4.3%). Ridinilazole maintained activity against all ribotypes and all strains resistant to any other agent tested. Ridinilazole showed excellent in vitro activity against C. difficile isolates collected between 2020 and 2021 in the United States, independent of ribotype.

Novel diamides inspired by protein kinase inhibitors as anti-Trypanosoma cruzi agents: in vitro and in vivo evaluations.

Background: Chagas disease is a life-threatening illness caused by Trypanosoma cruzi. The involvement of serine-/arginine-rich protein kinase in the T. cruzi life cycle is significant. Aims: To synthesize, characterize and evaluate the trypanocidal activity of diamides inspired by kinase inhibitor, SRPIN340. Material & Methods: Synthesis using a three-step process and characterization by infrared, nuclear magnetic resonance and high-resolution mass spectrometry were conducted. The selectivity index was obtained by the ratio of CC50/IC50 in two in vitro models. The most active compound, 3j, was evaluated using in vitro cytokine assays and assessing in vivo trypanocidal activity. Results: 3j activity in the macrophage J774 lineage showed an anti-inflammatory profile, and mice showed significantly reduced parasitemia and morbidity at low compound dosages. Conclusion: Novel diamide is active against T. cruzi in vitro and in vivo.

In Vitro Activity of Finafloxacin against Panels of Respiratory Pathogens.

This study determined the in vitro activity of finafloxacin against panels of bacterial strains, representative of those associated with infection in cystic fibrosis patients and predominately isolated from clinical cases of respiratory disease. Many of these isolates were resistant to various antimicrobials evaluated including the aminoglycosides, cephalosporins, carbapenems and fluoroquinolones. Broth microdilution assays were performed at neutral and acidic pH, to determine antimicrobial activity. Finafloxacin demonstrated superior activity at reduced pH for all of the bacterial species investigated, highlighting the requirement to determine the activity of antimicrobials in host-relevant conditions.

The Spicy Science of Dendrimers in the Realm of Cancer Nanomedicine: A Report from the COST Action CA17140 Nano2Clinic.

COST Action CA17140 Cancer Nanomedicine-from the bench to the bedside (Nano2Clinic,) is the first, pan-European interdisciplinary network of representatives from academic institutions and small and medium enterprises including clinical research organizations (CROs) devoted to the development of nanosystems carrying anticancer drugs from their initial design, preclinical testing of efficacy, pharmacokinetics and toxicity to the preparation of detailed protocols needed for the first phase of their clinical studies. By promoting scientific exchanges, technological implementation, and innovative solutions, the action aims at providing a timely instrument to rationalize and focus research efforts at the European level in dealing with the grand challenge of nanomedicine translation in cancer, one of the major and societal-burdening human pathologies. Within CA17140, dendrimers in all their forms (from covalent to self-assembling dendrons) play a vital role as powerful nanotheranostic agents in oncology; therefore, the purpose of this review work is to gather and summarize the major results in the field stemming from collaborative efforts in the framework of the European Nano2Clinic COST Action.

In Vitro Activity of Novel Topoisomerase Inhibitors against Francisella tularensis and Burkholderia pseudomallei.

Antimicrobial resistance is a global issue, and the investigation of alternative therapies that are not traditional antibiotics are warranted. Novel bacterial type II topoisomerase inhibitors (NBTIs) have recently emerged as a novel class of antibiotics with reduced potential for cross-resistance to fluoroquinolones due to their novel mechanism of action. This study investigated the in vitro activity of a series of cyclohexyl-oxazolidinone bacterial topoisomerase inhibitors against type strains of Francisella tularensis and Burkholderia pseudomallei. Broth microdilution, time-kill, and cell infection assays were performed to determine activity against these biothreat pathogens. Two candidates were identified that demonstrated in vitro activity in multiple assays that in some instances was equivalent to ciprofloxacin and doxycycline. These data warrant the further evaluation of these novel NBTIs and future iterations in vitro and in vivo.

High expression of antimicrobial peptides cathelicidin-BF in Pichia pastoris and verification of its activity.

Antibacterial peptides are endogenous polypeptides produced by multicellular organisms to protect the host against pathogenic microbes, they show broad spectrum antimicrobial activities against various microorganisms and possess low propensity for developing resistance. The purpose of this study is to develop recombinant antibacterial peptide cathelicidin-BF by genetic engineering and protein engineering technology, and study its antibacterial activity in vitro and in vivo, so as to provide reference for the production and application of recombinant antibacterial peptide cathelicidin-BF. In this study, on account of Pichia pastoris eukaryotic expression system, we expressed and prepared antibacterial peptide cathelicidin-BF. Then, the minimum inhibitory concentration of antibacterial peptide cathelicidin-BF and the comparison with the antibacterial activity of antibiotics were determined through the antibacterial experiment in vitro. Chickens as infection model were used to verify the antibacterial peptide activity in vivo. The results show that the bacteriostatic ability of antibacterial peptide cathelicidin-BF is similar to that of antibiotics in certain concentration, and can reach the treatment level of antibiotics. Although the mode of administration of antibacterial peptide is still limited, this study can provide reference for the future research of antibacterial peptide.

Comparison of In Vitro Activity of Ceftazidime-Avibactam and Imipenem-Relebactam against Clinical Isolates of Pseudomonas aeruginosa.

The role of novel ß-lactam/ß-lactamase inhibitor combinations in ceftazidime-nonsusceptible (CAZ-NS) and imipenem-nonsusceptible (IPM-NS) Pseudomonas aeruginosa has not been fully elucidated. This study evaluated the in vitro activity of novel ß-lactam/ß-lactamase inhibitor combinations against Pseudomonas aeruginosa clinical isolates, determined how avibactam restored ceftazidime activity, and compared the activity of ceftazidime-avibactam (CZA) and imipenem-relebactam (IMR) against KPC-producing P. aeruginosa. Similar high susceptibility rates for CZA, IMR, and ceftolozane-tazobactam (88.9% to 89.8%) were found for 596 P. aeruginosa clinical isolates from 11 hospitals in China, and a higher susceptibility rate to ceftazidime than imipenem was observed (73.5% versus 63.1%). For CAZ-NS and IPM-NS isolates, susceptibility rates for CZA, ceftolozane-tazobactam, and IMR were 61.5% (75/122), 54.9% (67/122), and 51.6% (63/122), respectively. For CAZ-NS, IPM-NS but CZA-susceptible isolates, 34.7% (26/75) harbored acquired ß-lactamases with KPC-2 predominant (n = 19), and 45.3% (34/75) presented overexpression of chromosomal ß-lactamase ampC. Among 22 isolates carrying KPC-2 carbapenemase alone, susceptibility rates to CZA and IMR were 86.4% (19/22) and 9.1% (2/22), respectively. Notably, 95% (19/20) of IMR-nonsusceptible isolates had an inactivating mutation of oprD gene. In conclusion, CZA, ceftolozane-tazobactam, and IMR exhibit high activity against P. aeruginosa, and CZA is more active than IMR against CAZ-NS and IPM-NS isolates as well as KPC-producing P. aeruginosa. Avibactam overcomes ceftazidime resistance engendered by KPC-2 enzyme and overexpressed AmpC. IMPORTANCE The emergence of antimicrobial resistance poses a particular challenge globally, and the concept of P. aeruginosa with "difficult-to-treat" resistance (DTR-P. aeruginosa) was proposed. Here, P. aeruginosa clinical isolates were highly susceptible to three ß-lactamase inhibitor combinations, CZA, IMR, and ceftolozane-tazobactam. The combination of KPC-2 enzyme and nonfunctional porin OprD contributed to IMR resistance in P. aeruginosa, and CZA was more active than IMR in fighting against KPC-2-producing P. aeruginosa. CZA also showed good activity against CAZ-NS and IPM-NS P. aeruginosa, primarily by inhibiting KPC-2 enzyme and overproduced AmpC, supporting the clinical use of CZA in the treatment of infections caused by DTR-P. aeruginosa.

In Vitro Activity of Cefiderocol Compared to Other Antimicrobials against a Collection of Metallo-Beta-Lactamase-Producing Gram-Negative Bacilli from Southern Spain.

In this study, we aimed to comparatively evaluate the in vitro activity of cefiderocol versus other antimicrobials against a well-characterized collection of metallo-beta-lactamase (MBL)-producing Gram-negative bacilli (MBL-GNB) isolates from hospitals in Andalusia, Spain. We recovered 232 MBL-GNB from Andalusian hospitals, including 160 Enterobacterales and 72 nonfermenting Gram-negative bacilli belonging to 44 different clones (2015 to 2020). Cefiderocol and comparator MICs were determined with commercial methods (UMIC [Bruker] and EUMDROXF [Sensititre; Thermo Fisher], respectively). EUCAST breakpoints were used for all antimicrobials tested, and CLSI also was used for cefiderocol. Control strains used were E. coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853. Cefiderocol showed potent in vitro activity against isolates tested, regardless of breakpoint (susceptibility rates, 85.3% for EUCAST versus 96.6% for CLSI, P < 0.001). MIC ranges for Enterobacterales and nonfermenting Gram-negative bacilli (NF-GNB) were ≤0.03 to 1 mg/L and 0.06 to 2 (IMP), 0.06 to 8 mg/L and 0.06 to 16 (VIM), 0.25 to 16 mg/L and 2 to 16 mg/L (NDM), respectively, and 0.25 to 8 mg/L for double MBL-producing Enterobacterales. By species, all cefiderocol-susceptible rates were over 90%, except Klebsiella oxytoca, Enterobacter cloacae, Escherichia coli, and Acinetobacter spp. Significant differences were observed comparing resistant isolates between Enterobacterales and NF-GNB by EUCAST (19.4% versus 4.2%, P < 0.01), but not by CLSI (4.4% versus 1.4%, P = 0.2). Cefiderocol was the most active antimicrobial tested. Cefiderocol showed excellent in vitro activity against MBL-GNB, especially NF-GNB; almost all isolates resistant to comparators were susceptible. IMPORTANCE This article demonstrates the efficacy of cefiderocol against a large collection of well-characterized metallo-beta-lactamase-producing isolates, some of them even producing double carbapenemases. Furthermore, cefiderocol activity is compared to other novel broad-spectrum antimicrobials with activity against carbapenemases.

Docking, Synthesis, and In vitro Anti-depressant Activity of Certain Isatin Derivatives.

BACKGROUND: In vitro, the molecular docking method has been suggested for estimating the biological affinity of the pharmacophores with physiologically active compounds. It is the latter stage in molecular docking, and the docking scores are examined using the AutoDock 4.2 tool program. The chosen compounds can be evaluated for in vitro activity based on the binding scores, and the IC50 values can be computed. OBJECTIVE: The purpose of this work was to create methyl isatin compounds as potential antidepressants, compute physicochemical characteristics, and carry out docking analysis. METHODS: The protein data bank of the RCSB (Research Collaboratory for Structural Bioinformatics) was used to download the PDB structures of monoamine oxidase (PDB ID: 2BXR) and indoleamine 2,3-dioxygenase (PDB ID: 6E35). Based on the literature, methyl isatin derivatives were chosen as the lead chemicals. By determining their IC50 values, the chosen compounds were tested for in vitro anti-depressant activity. RESULTS: The binding scores for the interactions of SDI 1 and SD 2 with indoleamine 2,3 dioxygenase were found to be -10.55 kcal/mol and -11.08 kcal/mol, respectively, while the scores for their interactions with monoamine oxidase were found to be -8.76 kcal/mol and -9.28 kcal/mol, respectively, using AutoDock 4.2. The relationship between biological affinity and pharmacophore electrical structure was examined using the docking technique. The chosen compounds were tested for their ability to inhibit MAO, and the IC50 values for each were found to be 51.20 and 56, respectively. CONCLUSION: This investigation has identified many novel and effective MAO-A inhibitors from the family of chemicals known as methyl isatin derivatives. Lead optimization was applied to the SDI 1 and SDI 2 derivatives. The superior bioactivity, pharmacokinetic profile, BBB penetration, pre-ADMET profiles, such as HIA (human intestinal absorption) and MDCK (Madin-Darby canine kidney), plasma protein binding, toxicity assessment, and docking outcomes, have been obtained. According to the study, synthesised isatin 1 and SDI 2 derivatives exhibited a stronger MAO inhibitory activity and effective binding energy, which may help prevent stress-induced depression and other neurodegenerative disorders caused by a monoamine imbalance.

Characterization of bioactives and in vitro biological activity from Protaetia brevitarsis larval extracts obtained by different pretreatment extractions.

Intestinal contents affect the characterization of edible insect bioactive compounds. Two empty intestine methods, namely, traditional static method (TSM) or salt immersion stress method (SISM), associated with extraction solvents water (W), 50 % water-ethanol (W:E) or 100 % ethanol (E), were used to obtain six Protaetia brevitarsis larval extracts. The total flavonoid content (TFC) in the W:E extracts was significantly higher than that in the W and E extracts, with TSM-W:E the highest (p < 0.05). The relative contents of 132 bioactive compounds, especially p-hydroxyphenylacetic acid, citric acid, and dehydroepiandrosterone, were different between TSM-W and SISM-W. TSM-W:E had significantly higher 2,2-diphenyl-1-picrylhydroxy· (DPPH) scavenging and pancreatic lipase (PL) inhibitory activity than SISM-W:E (p < 0.05). DPPH scavenging and PL inhibitory activities were highly correlated with TFC and carbohydrates, respectively. Thus, bioactive compounds in P. brevitarsis extracts can be obtained selectively using pretreatment methods, which might be beneficial for high-value utilization of P. brevitarsis.

Evaluation of in-vitro susceptibility of ß-lactam-resistant Gram-negative bacilli to ceftazidime-avibactam and ceftolozane-tazobactam from clinical samples of a general hospital in southern Brazil

ABSTRACT Background: The spread of carbapenemase- and extended-spectrum β-lactamase (ESBL)-producing gram-negative bacilli (GNB) represent a global public health threat that limits therapeutic options for hospitalized patients. This study aimed to evaluate the in-vitro susceptibility of β-lactam-resistant GNB to ceftazidime-avibactam (C/A) and ceftolozane-tazobactam (C/T), and investigate the molecular determinants of resistance. Methods: Overall, 101 clinical isolates of Enterobacterales and Pseudomonas aeruginosa collected from a general hospital in Brazil were analyzed. Susceptibility to the antimicrobial agents was evaluated using an automated method, and the minimum inhibitory concentrations (MIC50/90) of C/A and C/T were determined using Etest®. The β-lactamase-encoding genes were investigated using polymerase chain reaction. Results: High susceptibility to C/A and C/T was observed among ESBL-producing Enterobacterales (100% and 97.3% for CLSI and 83.8% for BRCAST, respectively) and carbapenem-resistant P. aeruginosa (92.3% and 87.2%, respectively). Carbapenemase-producing Klebsiella pneumoniae exhibited high resistance to C/T (80%- CLSI or 100%- BRCAST) but high susceptibility to C/A (93.4%). All carbapenem-resistant K. pneumoniae isolates were susceptible to C/A, whereas only one isolate was susceptible to C/T. Both antimicrobials were inactive against metallo-β-lactamase-producing K. pneumoniae isolates. Resistance genes were concomitantly identified in 44 (44.9%) isolates, with bla CTX-M and bla SHV being the most common. Conclusions: C/A and C/T were active against microorganisms with β-lactam-resistant phenotypes, except when resistance was mediated by metallo-β-lactamases. Most C/A- and C/T-resistant isolates concomitantly carried two or more β-lactamase-encoding genes (62.5% and 77.4%, respectively).

Cloning and functional analysis of IPI gene from Fritillaria unibracteata Hsiao et K. C. Hsia / 药学学报

An open reading frame (ORF) of isopentenyl-diphosphate delta isomerase gene (FuIPI) was cloned from Fritillaria unibracteata Hsiao et K. C. Hsia. (F. unibracteata). Furthermore, the bioinformatics and functional analyses of FuIPI were performed in this study. The result showed that, the ORF of FuIPI gene was 825 bp, encoding a polypeptide of 274 amino acids in length, with a relative molecular mass of about 31 kD and a theoretical isoelectric point of 5.61. Sequence analysis showed that FuIPI contained conserved structural domains and key residues involved in the catalyzing process. The phylogenetic analysis exhibited that FuIPI was closely related to IPIs of Dendrobium officinale and Musa acuminate. Real-time PCR analysis showed that FuIPI was distributed in different tissues of F. unibracteata, but had the highest transcriptional level in leaves, followed by stems, bulbs, and flowers. Furthermore, the FuIPI protein was successfully expressed in Escherichia coli BL21(DE3). The purified FuIPI protein successfully catalyzed the conversion from isopentenyl diphosphate (IPP) to dimethylallyl pyrophosphate (DMAPP). The above results provided a theoretical basis for further investigation of the molecular role of FuIPI in the biosynthesis of alkaloids.