Design, synthesis, characterization and in vitro evaluation of some novel thiol-substituted 1,3,4-oxadiazoles as GlmS inhibitors

The development of novel medications with previously unidentified action mechanisms is required due to the increasing in antibiotic resistance amongst dangerous microbes. The major goal of the research was to develop in silico and in vitro antibacterial methods for designing an active thiol substituted oxadiazole inhibitor targeting gram-negative and gram-positive bacteria's GlmS receptor. 1,3,4-Oxadiazole was proposed as a scaffold, and the possibility of its synthesis was examined. The least amount of free energy in the ligand configurations was chosen. Analyses of the novel molecules' characteristics were done using ADMET studies. There were four distinct reactions used in the synthesis processes. As the first reagent, substituted carboxylic acids were utilized. Synthesized compounds were characterized by spectral studies and minimum inhibitory concentration was evaluated by in vitro antibacterial examinations of synthesized compounds. Ciprofloxacin served as the study's reference drug. Based on in vitro studies and in silico molecular docking, ROS1-4 established strong binding energy, while ROS3 revealed significant antibacterial activity. These findings support the hypothesis that the proposed scaffold significantly inhibits the GlmS receptor protein

Exogenous Glucose Administration Impairs Glucose Tolerance and Pancreatic Insulin Secretion during Acute Sepsis in Non-Diabetic Mice

Objectives:The development of hyperglycemia and the use of early parenteral feeding are associated with poor outcomes in critically ill patients. We therefore examined the impact of exogenous glucose administration on the integrated metabolic function of endotoxemic mice using our recently developed frequently sampled intravenous glucose tolerance test (FSIVGTT). We next extended our findings using a cecal ligation and puncture (CLP) sepsis model administered early parenteral glucose support.Methods:Male C57BL/6J mice, 8-12 weeks, were instrumented with chronic indwelling arterial and venous catheters. Endotoxemia was initiated with intra-arterial lipopolysaccharide (LPS; 1 mg/kg) in the presence of saline or glucose infusion (100 μL/hr), and an FSIVGTT was performed after five hours. In a second experiment, catheterized mice underwent CLP and the impact of early parenteral glucose administration on glucose homeostasis and mortality was assessed over 24 hrs.Measurements:And MAIN RESULTS: Administration of LPS alone did not impair metabolic function, whereas glucose administration alone induced an insulin sensitive state. In contrast, LPS and glucose combined caused marked glucose intolerance and insulin resistance and significantly impaired pancreatic insulin secretion. Similarly, CLP mice receiving parenteral glucose developed fulminant hyperglycemia within 18 hrs (all > 600 mg/dl) associated with increased systemic cytokine release and 40% mortality, whereas CLP alone (85 ± 2 mg/dL) or sham mice receiving parenteral glucose (113 ± 3 mg/dL) all survived and were not hyperglycemic. Despite profound hyperglycemia, plasma insulin in the CLP glucose-infused mice (3.7 ± 1.2 ng/ml) was not higher than sham glucose infused mice (2.1 ± 0.3 ng/ml).Conclusions:The combination of parenteral glucose support and the systemic inflammatory response in the acute phase of sepsis induces profound insulin resistance and impairs compensatory pancreatic insulin secretion, leading to the development of fulminant hyperglycemia. © 2013 Watanabe et al

Carbon Dioxide Utilisation -The Formate Route

UIDB/50006/2020 CEEC-Individual 2017 Program Contract.The relentless rise of atmospheric CO2 is causing large and unpredictable impacts on the Earth climate, due to the CO2 significant greenhouse effect, besides being responsible for the ocean acidification, with consequent huge impacts in our daily lives and in all forms of life. To stop spiral of destruction, we must actively reduce the CO2 emissions and develop new and more efficient “CO2 sinks”. We should be focused on the opportunities provided by exploiting this novel and huge carbon feedstock to produce de novo fuels and added-value compounds. The conversion of CO2 into formate offers key advantages for carbon recycling, and formate dehydrogenase (FDH) enzymes are at the centre of intense research, due to the “green” advantages the bioconversion can offer, namely substrate and product selectivity and specificity, in reactions run at ambient temperature and pressure and neutral pH. In this chapter, we describe the remarkable recent progress towards efficient and selective FDH-catalysed CO2 reduction to formate. We focus on the enzymes, discussing their structure and mechanism of action. Selected promising studies and successful proof of concepts of FDH-dependent CO2 reduction to formate and beyond are discussed, to highlight the power of FDHs and the challenges this CO2 bioconversion still faces.publishersversionpublishe

Increasing the bactofection capacity of a mammalian expression vector by removal of the f1 ori

Bacterial-mediated cancer therapy has shown great promise in in vivo tumour models with increased survival rates post-bacterial treatment. Improving efficiency of bacterial-mediated tumour regression has focused on controlling and exacerbating bacterial cytotoxicity towards tumours. One mechanism that has been used to carry this out is the process of bactofection where post-invasion, bacteria deliver plasmid-borne mammalian genes into target cells for expression. Here we utilised the cancer-targeting Salmonella Typhimurium strain, SL7207, to carry out bactofection into triple negative breast cancer MDA-MB-231 cells. However, we noted that post-transformation with the commonly used mammalian expression vector pEGFP, S. Typhimurium became filamentous, attenuated and unable to invade target cells efficiently. Filamentation did not occur in Escherichia coli-transformed with the same plasmid. Further investigation identified the region inducing S. Typhimurium filamentation as being the f1 origin of replication (f1 ori), an artefact of historic use of mammalian plasmids for single stranded DNA production. Other f1 ori-containing plasmids also induced the attenuated phenotype, while removal of the f1 ori from pEGFP restored S. Typhimurium virulence and increased the bactofection capacity. This work has implications for interpretation of prior bactofection studies employing f1 ori-containing plasmids in S. Typhimurium, while also indicating that future use of S. Typhimurium in targeting tumours should avoid the use of these plasmids

RETENTION OF LABEL OF LEUCINE-U-C-14 IN THE HEMOLYMPH OF PILA-GLOBOSA (SWAINSON) AS A FUNCTION OF SEX AND LONG-TERM ESTIVATION

Volume: 24Start Page: 373End Page: 37

Design, synthesis, characterization and in vitro evaluation of some novel thiol-substituted 1,3,4-oxadiazoles as GlmS inhibitors

148-155The development of novel medications with previously unidentified action mechanisms is required due to the increasing in antibiotic resistance amongst dangerous microbes. The major goal of the research was to develop in silico and in vitro antibacterial methods for designing an active thiol substituted oxadiazole inhibitor targeting gram-negative and grampositive bacteria's GlmS receptor. 1,3,4-Oxadiazole was proposed as a scaffold, and the possibility of its synthesis was examined. The least amount of free energy in the ligand configurations was chosen. Analyses of the novel molecules' characteristics were done using ADMET studies. There were four distinct reactions used in the synthesis processes. As the first reagent, substituted carboxylic acids were utilized. Synthesized compounds were characterized by spectral studies and minimum inhibitory concentration was evaluated by in vitro antibacterial examinations of synthesized compounds. Ciprofloxacin served as the study's reference drug. Based on in vitro studies and in silico molecular docking, ROS1-4 established strong binding energy, while ROS3 revealed significant antibacterial activity. These findings support the hypothesis that the proposed scaffold significantly inhibits the GlmS receptor protein

Case Report - Fatal group a streptococcal meningitis in an adult

Despite the recent resurgence in reports of invasive Group A Streptococcal (GAS) infections worldwide, it remains a rare cause of pyogenic meningitis both in children and adults. We report a case of fatal GAS meningitis in a healthy adult emphasizing the need for clinicians to be aware of its fulminant course, prompting early diagnosis and treatment. There is also a need to consider postexposure chemoprophylaxis in close contacts of such cases