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JACS Au Jun 2024The first total synthesis of the repeating units of the -antigens of ATCC 27577, O10, and O19 was achieved via a linear glycosylation strategy. This also represents the...
The first total synthesis of the repeating units of the -antigens of ATCC 27577, O10, and O19 was achieved via a linear glycosylation strategy. This also represents the first synthesis of an oligosaccharide containing an α-linked -acetyl-l-galactosaminuronic acid (l-GalNAcA) unit. All of the glycosyl linkages, including three challenging 1,2--glycosidic bonds of amino sugars, were effectively constructed with high to exclusive stereoselectivity, while orthogonal protection tactics were employed to facilitate regioselective glycosylations and the introduction of a variety of functionalities. An acetyl group migration phenomenon was found during the synthesis of the -acylated repeating unit of the ATCC 27577 antigen. All synthetic targets carried an amino functional group in the linker at the reducing end, thus facilitating further regioselective elaboration and biological studies. The synthetic strategy established here should be useful for the preparation of other similar oligosaccharides.
PubMed: 38938791
DOI: 10.1021/jacsau.4c00321 -
Open Veterinary Journal May 2024This research describes the methodology used for the preparation of selenium nanoparticles from and their administration to lambs for lipid profile checking,...
BACKGROUND
This research describes the methodology used for the preparation of selenium nanoparticles from and their administration to lambs for lipid profile checking, administration of selenium nanoparticles as a medication in lambs results in hypolipidemia.
AIMED
The study aimed to investigate the potential of selenium nanoparticles in improving lipid profiles in lambs.
METHODS
Healthy lambs ( = 10) of similar age and weight were selected for the study. The animals were housed in individual pens with free access to water and a standard diet. The lambs were randomly divided into two groups: the control group ( = 5) and the treatment group ( = 5). The control group received a standard diet, while the treatment group received the same diet and oral administrated with selenium nanoparticles at 0.1 mg/kg body weight. The administration was carried out daily for a period of 8 weeks. Blood samples were collected from the jugular vein of each lamb at the beginning of the study (baseline) and at the end of the 2 weeks treatment period. The samples were collected in vacutainer tubes and allowed to clot. Serum was separated by centrifugation at 3,000 rpm for 10 minutes and stored at -80°C for estimation of lipid profile total cholesterol (TC), triglyceride, high-density lipoprotein (HDL), and low-density lipoprotein (LDL). The serum samples were used for the estimation of lipid profile levels using an enzymatic colorimetric method. The absorbance was measured at 540 nm using a spectrophotometer.
RESULTS
The results showed a significant decrease in serum TC, triglyceride, and very-low-density lipoprotein cholesterol levels after selenium nanoparticle supplementation compared to the control group ( < 0.05), the results indicated a significant increase in serum HDL levels after selenium nanoparticle supplementation compared to the control group ( < 0.05). This indicates that selenium nanoparticle supplementation has a beneficial effect on reducing TC levels in lambs.
CONCLUSION
The conclusion section will summarize the findings of the study and highlight the potential of selenium nanoparticles in improving lipid profiles in lambs. The implications of the study for animal nutrition and health will be discussed, along with the need for further research in this area.
Topics: Animals; Selenium; Male; Nanoparticles; Lipids; Sheep; Pseudomonas aeruginosa; Sheep, Domestic
PubMed: 38938439
DOI: 10.5455/OVJ.2024.v14.i5.10 -
Health Technology Assessment... Jun 2024To limit the use of antimicrobials without disincentivising the development of novel antimicrobials, there is interest in establishing innovative models that fund...
BACKGROUND
To limit the use of antimicrobials without disincentivising the development of novel antimicrobials, there is interest in establishing innovative models that fund antimicrobials based on an evaluation of their value as opposed to the volumes used. The aim of this project was to evaluate the population-level health benefit of cefiderocol in the NHS in England, for the treatment of severe aerobic Gram-negative bacterial infections when used within its licensed indications. The results were used to inform the National Institute for Health and Care Excellence guidance in support of commercial discussions regarding contract value between the manufacturer and NHS England.
METHODS
The health benefit of cefiderocol was first derived for a series of high-value clinical scenarios. These represented uses that were expected to have a significant impact on patients' mortality risks and health-related quality of life. The clinical effectiveness of cefiderocol relative to its comparators was estimated by synthesising evidence on susceptibility of the pathogens of interest to the antimicrobials in a network meta-analysis. Patient-level costs and health outcomes of cefiderocol under various usage scenarios compared with alternative management strategies were quantified using decision modelling. Results were reported as incremental net health effects expressed in quality-adjusted life-years, which were scaled to 20-year population values using infection number forecasts based on data from Public Health England. The outcomes estimated for the high-value clinical scenarios were extrapolated to other expected uses for cefiderocol.
RESULTS
Among isolates with the metallo-beta-lactamase resistance mechanism, the base-case network meta-analysis found that cefiderocol was associated with a lower susceptibility relative to colistin (odds ratio 0.32, 95% credible intervals 0.04 to 2.47), but the result was not statistically significant. The other treatments were also associated with lower susceptibility than colistin, but the results were not statistically significant. In the metallo-beta-lactamase base-case network meta-analysis, cefiderocol was associated with a lower susceptibility relative to colistin (odds ratio 0.44, 95% credible intervals 0.03 to 3.94), but the result was not statistically significant. The other treatments were associated with no susceptibility. In the base case, patient-level benefit of cefiderocol was between 0.02 and 0.15 quality-adjusted life-years, depending on the site of infection, the pathogen and the usage scenario. There was a high degree of uncertainty surrounding the benefits of cefiderocol across all subgroups. There was substantial uncertainty in the number of infections that are suitable for treatment with cefiderocol, so population-level results are presented for a range of scenarios for the current infection numbers, the expected increases in infections over time and rates of emergence of resistance. The population-level benefits varied substantially across the base-case scenarios, from 896 to 3559 quality-adjusted life-years over 20 years.
CONCLUSION
This work has provided quantitative estimates of the value of cefiderocol within its areas of expected usage within the NHS.
LIMITATIONS
Given existing evidence, the estimates of the value of cefiderocol are highly uncertain.
FUTURE WORK
Future evaluations of antimicrobials would benefit from improvements to NHS data linkages; research to support appropriate synthesis of susceptibility studies; and application of routine data and decision modelling to assess enablement value.
STUDY REGISTRATION
No registration of this study was undertaken.
FUNDING
This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment Policy Research Programme (NIHR award ref: NIHR135591), conducted through the Policy Research Unit in Economic Methods of Evaluation in Health and Social Care Interventions, PR-PRU-1217-20401, and is published in full in ; Vol. 28, No. 28. See the NIHR Funding and Awards website for further award information.
Topics: Humans; Cephalosporins; Anti-Bacterial Agents; Quality-Adjusted Life Years; Cost-Benefit Analysis; England; Technology Assessment, Biomedical; Cefiderocol; Gram-Negative Bacterial Infections; State Medicine; Quality of Life
PubMed: 38938145
DOI: 10.3310/YGWR4511 -
Environmental Science & Technology Jun 2024Waterborne pathogens invariably present considerable threats to public health. The quorum sensing (QS) system is instrumental in coordinating bacterial growth and...
Waterborne pathogens invariably present considerable threats to public health. The quorum sensing (QS) system is instrumental in coordinating bacterial growth and metabolisms. However, the responses and regulatory mechanisms of bacteria to various disinfection technologies through quorum sensing are still unclear. This study examines the inactivation effect of chlorination and ozonation on biofilms and planktonic cells of QS signaling-deficient mutants of . Cell counting and viability assessment revealed that the combined disinfection of chlorine and ozone was the most effective for inactivating planktonic within 10 min of exposure. Additionally, microfluidic chip culture demonstrated that the secretion of quinolone signals escalated biofilms' disinfection resistance. Disinfection exposure significantly altered the gene expression of wild-type strains and QS signaling-deficient mutants. Moreover, the QS system triggered multilayered gene expression programs as a responsive protection to disinfectant exposure, including oxidative stress, ribosome synthesis, and the nutrient absorption of bacteria. These insights broaden our understanding of bacterial QS in response to disinfection, promising potential strategies toward efficient disinfection processes.
PubMed: 38937254
DOI: 10.1021/acs.est.3c08305 -
Metabolic Engineering Jun 2024Biological conversion of lignin from biomass offers a promising strategy for sustainable production of fuels and chemicals. However, aromatic compounds derived from...
Biological conversion of lignin from biomass offers a promising strategy for sustainable production of fuels and chemicals. However, aromatic compounds derived from lignin commonly contain methoxy groups, and O-demethylation of these substrates is often a rate-limiting reaction that influences catabolic efficiency. Several enzyme families catalyze aromatic O-demethylation, but they are rarely compared in vivo to determine an optimal biocatalytic strategy. Here, two pathways for aromatic O-demethylation were compared in Pseudomonas putida KT2440. The native Rieske non-heme iron monooxygenase (VanAB) and, separately, a heterologous tetrahydrofolate-dependent demethylase (LigM) were constitutively expressed in P. putida, and the strains were optimized via adaptive laboratory evolution (ALE) with vanillate as a model substrate. All evolved strains displayed improved growth phenotypes, with the evolved strains harboring the native VanAB pathway exhibiting growth rates ∼1.8x faster than those harboring the heterologous LigM pathway. Enzyme kinetics and transcriptomics studies investigated the contribution of selected mutations toward enhanced utilization of vanillate. The VanAB-overexpressing strains contained the most impactful mutations, including those in VanB, the reductase for vanillate O-demethylase, PP_3494, a global regulator of vanillate catabolism, and fghA, involved in formaldehyde detoxification. These three mutations were combined into a single strain, which exhibited approximately 5x faster vanillate consumption than the wild-type strain in the first 8 h of cultivation. Overall, this study illuminates the details of vanillate catabolism in the context of two distinct enzymatic mechanisms, yielding a platform strain for efficient O-demethylation of lignin-related aromatic compounds to value-added products.
PubMed: 38936762
DOI: 10.1016/j.ymben.2024.06.009 -
Chemosphere Jun 2024This research investigated the comparative efficacy of sulfamic acid (SA) and phytic acid (PA), both individually and in combination, for treating potential foodborne...
This research investigated the comparative efficacy of sulfamic acid (SA) and phytic acid (PA), both individually and in combination, for treating potential foodborne pathogens and pre-formed foulants. Pathogens studied included Listeria monocytogenes, E. coli DH5α, Salmonella Typhimurium, Staphylococcus aureus, and vegetative Bacillus cereus, in suspended aqueous solutions, as well as Pseudomonas aeruginosa biofilm on quartz glass surfaces. Inactivation kinetics for Listeria monocytogenes revealed concentration-dependent rate constants (k) of 6.6(±0.2)×10 M and 2.8(±0.1)×10 M for single treatments of SA and PA, respectively, and ranged from 6.9(±0.3) to 50.7(±2.3)×10 M for combined treatments with PA pre-treatment concentrations of 75-758 μM. Observable cellular abnormalities in Listeria monocytogenes, such as membrane vesiculation, chelation, cellular disruption, biomolecule leakage, and lipid peroxidation, were identified after exposure to PA or SA, either individually or in combination. The optimized combined treatment of PA and SA achieved significant removal (i.e., >3-log; 99.9%) of potential foodborne pathogens under simulated food-washing process conditions. Additionally, over 90% descaling efficacy was observed for pre-formed foulants such as CaCO precipitates and Pseudomonas aeruginosa biofilm on quartz glass surfaces with the combined treatment. These findings provide novel insights into the versatile utility of PA and SA for optimizing combinational water disinfection systems and addressing (in)organic foulant scaling on surfaces in the food processing industry.
PubMed: 38936490
DOI: 10.1016/j.chemosphere.2024.142706 -
Journal of Hazardous Materials Jun 2024Cd is highly mobile, non-essential trace element, that has become serious environmental issue due to its elevated concentration in soil. The present study was taken up...
Integrated transcriptomic and physio-molecular studies unveil the melatonin and PGPR induced protection to photosynthetic attributes in Brassica juncea L. under cadmium toxicity.
Cd is highly mobile, non-essential trace element, that has become serious environmental issue due to its elevated concentration in soil. The present study was taken up to work out salutary effect of melatonin (Mlt) and PGPR ((Pseudomonas putida (Pp), Pseudomonas fluorescens (Pf) in 10 days old Cd stressed (0.3 mM) Brassica juncea L. seedlings. The present work investigated growth characteristics, photosynthetic pigments, secondary metabolites in melatonin-PGPR inoculated B. juncea seedlings. It was backed by molecular studies entailing RT-PCR and transcriptomic analyses. Our results revealed, substantial increase in photosynthetic pigments and secondary metabolites, after treatment with melatonin, P.putida, P. fluorescens in Cd stressed B. juncea seedlings, further validated with transcriptome analysis. Comparative transcriptome analyses identified 455, 5953, 3368, 2238 upregulated and 4921, 430, 137, 27 down regulated DEGs, Cn-vs-Cd, Cd-vs-Mlt, Cd-vs-Mlt-Pp-Pf, Cd-vs-Mlt-Pp-Pf-Cd comparative groups respectively. In depth exploration of genome analyses (Gene ontology, Kyoto encyclopaedia of genes), revealed that Cd modifies the expression patterns of most DEGs mainly associated to photosystem and chlorophyll synthesis. Also, gene expression studies for key photosynthetic genes (psb A, psb B, CHS, PAL, and PSY) suggested enhanced expression in melatonin-rhizobacteria treated Cd stressed B. juncea seedlings. Overall, results provide new insights into probable mechanism of Mlt-PGPR induced protection to photosynthesis in Cd stressed B. juncea plants.
PubMed: 38936187
DOI: 10.1016/j.jhazmat.2024.134875 -
Bioorganic Chemistry Jun 2024Di-branched and tetra-branched versions of a previously reported analogue of the lipopeptide battacin were successfully synthesised using thiol-maleimide click and 1, 2,...
Di-branched and tetra-branched versions of a previously reported analogue of the lipopeptide battacin were successfully synthesised using thiol-maleimide click and 1, 2, 3-triazole click chemistry. Antimicrobial studies against drug resistant clinical isolates of Escherichia coli (ESBL E. coli Ctx-M14), Pseudomonas aeruginosa (P. aeruginosa Q502), and Methicillin resistant Staphylococcus aureus (MRSA ATCC 33593), as well as clinically isolated Acinetobacter baumannii (A. baumannii ATCC 19606), and P. aeruginosa (ATCC 27853), revealed that the dendrimeric peptides have antimicrobial activity in the low micromolar range (0.5 -- 4 μM) which was 10 times more potent than the monomer peptides. Under high salt concentrations (150 mM NaCl, 2 mM MgCl, and 2.5 mM CaCl) the di-branched lipopeptides retained their antimicrobial activity while the monomer peptides were not active (>100 μM). The di-branched triazole click lipopeptide, Peptide 12, was membrane lytic, showed faster killing kinetics, and exhibited antibiofilm activity against A. baumannii and MRSA and eradicated > 85 % preformed biofilms at low micromolar concentrations. The di-branched analogues were > 30-fold potent than the monomers against Candida albicans. Peptide 12 was not haemolytic (HC10 = 932.12 μM) and showed up to 40-fold higher selectivity against bacteria and fungi than the monomer peptide. Peptide 12 exhibited strong proteolytic stability (>80 % not degraded) in rat serum over 24 h whereas > 95 % of the thiol-maleimide analogue (Peptide 10) was degraded. The tetra-branched peptides showed comparable antibacterial potency to the di-branched analogues. These findings indicate that dual branching using triazole click chemistry is a promising strategy to improve the antimicrobial activity and proteolytic stability of battacin based lipopeptides. The information gathered can be used to build effective antimicrobial dendrimeric peptides as new peptide antibiotics.
PubMed: 38936047
DOI: 10.1016/j.bioorg.2024.107567 -
The Journal of Physical Chemistry. B Jun 2024Antimicrobial resistance in bacteria often arises from their ability to actively identify and expel toxic compounds. The bacterium strain DOT-T1E utilizes its TtgABC...
Antimicrobial resistance in bacteria often arises from their ability to actively identify and expel toxic compounds. The bacterium strain DOT-T1E utilizes its TtgABC efflux pump to confer robust resistance against antibiotics, flavonoids, and organic solvents. This resistance mechanism is intricately regulated at the transcriptional level by the TtgR protein. Through molecular dynamics and alchemical free energy simulations, we systematically examine the binding of seven flavonoids and their derivatives with the TtgR transcriptional regulator. Our simulations reveal distinct binding geometries and free energies for the flavonoids in the active site of the protein, which are driven by a range of noncovalent forces encompassing van der Waals, electrostatic, and hydrogen bonding interactions. The interplay of molecular structures, substituent patterns, and intermolecular interactions effectively stabilizes the bound flavonoids, confining their movements within the TtgR binding pocket. These findings yield valuable insights into the molecular determinants that govern ligand recognition in TtgR and shed light on the mechanism of antimicrobial resistance in DOT-T1E.
PubMed: 38935925
DOI: 10.1021/acs.jpcb.4c02303 -
Microbial Ecology Jun 2024Antimicrobial resistance (AMR) is a major public health threat, exacerbated by the ability of bacteria to rapidly disseminate antimicrobial resistance genes (ARG). Since...
Antimicrobial resistance (AMR) is a major public health threat, exacerbated by the ability of bacteria to rapidly disseminate antimicrobial resistance genes (ARG). Since conjugative plasmids of the incompatibility group P (IncP) are ubiquitous mobile genetic elements that often carry ARG and are broad-host-range, they are important targets to prevent the dissemination of AMR. Plasmid-dependent phages infect plasmid-carrying bacteria by recognizing components of the conjugative secretion system as receptors. We sought to isolate plasmid-dependent phages from wastewater using an avirulent strain of Salmonella enterica carrying the conjugative IncP plasmid pKJK5. Irrespective of the site, we only obtained bacteriophages belonging to the genus Alphatectivirus. Eleven isolates were sequenced, their genomes analyzed, and their host range established using S. enterica, Escherichia coli, and Pseudomonas putida carrying diverse conjugative plasmids. We confirmed that Alphatectivirus are abundant in domestic and hospital wastewater using culture-dependent and culture-independent approaches. However, these results are not consistent with their low or undetectable occurrence in metagenomes. Therefore, overall, our results emphasize the importance of performing phage isolation to uncover diversity, especially considering the potential of plasmid-dependent phages to reduce the spread of ARG carried by conjugative plasmids, and to help combat the AMR crisis.
Topics: Plasmids; Wastewater; Bacteriophages; Genome, Viral; Escherichia coli; Host Specificity; Pseudomonas putida; Salmonella enterica; Phylogeny
PubMed: 38935220
DOI: 10.1007/s00248-024-02401-3