scholarly journals Practical Synthesis of Iboxamycin, a Potent Antibiotic Candidate, in Amounts Suitable for Studies in Animal Infection Models

2021 ◽  
Author(s):  
Jeremy Mason ◽  
Daniel W. Terwilliger ◽  
Aditya R. Pote ◽  
Andrew G. Myers
Keyword(s):  
Reduction Reaction ◽  
Murine Models ◽  
One Pot ◽  
Ring Fusion ◽  
Negishi Coupling ◽  
Synthetic Strategy ◽  
Infection Models ◽  
Animal Infection ◽  
Practical Synthesis

A gram-scale synthesis of iboxamycin, an antibiotic candidate bearing a fused bicyclic amino acid residue, is presented. A pivotal transformation in the route involves an intramolecular hydrosilylation–oxidation sequence to set the ring-fusion stereocenters of the bicyclic scaffold. Other notable features of the synthesis include a high-yielding, highly diastereoselective alkylation of a pseudoephenamine amide, a convergent sp<sup>3</sup>–sp<sup>2</sup> Negishi coupling, and a one-pot transacetalization–reduction reaction to form the target compound’s oxepane ring. Implementation of this synthetic strategy has provided ample quantities of iboxamycin to allow for its <i>in vivo</i> profiling in murine models of infection.

scholarly journals Practical Synthesis of Iboxamycin, a Potent Antibiotic Candidate, in Amounts Suitable for Studies in Animal Infection Models

2021 ◽  
Author(s):  
Jeremy Mason ◽  
Daniel W. Terwilliger ◽  
Aditya R. Pote ◽  
Andrew G. Myers
Keyword(s):  
Reduction Reaction ◽  
Murine Models ◽  
One Pot ◽  
Ring Fusion ◽  
Negishi Coupling ◽  
Synthetic Strategy ◽  
Infection Models ◽  
Animal Infection ◽  
Practical Synthesis

A gram-scale synthesis of iboxamycin, an antibiotic candidate bearing a fused bicyclic amino acid residue, is presented. A pivotal transformation in the route involves an intramolecular hydrosilylation–oxidation sequence to set the ring-fusion stereocenters of the bicyclic scaffold. Other notable features of the synthesis include a high-yielding, highly diastereoselective alkylation of a pseudoephenamine amide, a convergent sp<sup>3</sup>–sp<sup>2</sup> Negishi coupling, and a one-pot transacetalization–reduction reaction to form the target compound’s oxepane ring. Implementation of this synthetic strategy has provided ample quantities of iboxamycin to allow for its <i>in vivo</i> profiling in murine models of infection.

scholarly journals In Vivo Efficacy of Novel Monobactam LYS228 in Murine Models of Carbapenemase-Producing Klebsiella pneumoniae Infection

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
W. J. Weiss ◽  
M. E. Pulse ◽  
P. Nguyen ◽  
E. J. Growcott
Keyword(s):  
Klebsiella Pneumoniae ◽  
Clinical Development ◽  
Murine Models ◽  
Bacterial Burden ◽  
In Vivo Efficacy ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Infection Models ◽  
Resistant Strains

ABSTRACT LYS228 has potent antibacterial activity against carbapenem-resistant strains of Enterobacteriaceae. LYS228 was efficacious in neutropenic thigh models established with Klebsiella pneumoniae producing KPC-2 or NDM-1; pretreatment with uranyl nitrate considerably shifted calculated static doses of LYS228. In murine ascending pyelonephritis, LYS228 reduced bacterial burden in kidney, urine, and bladder. The successful treatment of murine infection models established with carbapenem-resistant K. pneumoniae further supports the clinical development of LYS228.

A rational design of carbon-supported dispersive Pt-based octahedra as efficient oxygen reduction reaction catalysts

2014 ◽  
Vol 7 (9) ◽  
pp. 2957-2962 ◽  
Author(s):  
Xiaoqing Huang ◽  
Zipeng Zhao ◽  
Yu Chen ◽  
Enbo Zhu ◽  
Mufan Li ◽  
...  
Keyword(s):  
Oxygen Reduction Reaction ◽  
Oxygen Reduction ◽  
Rational Design ◽  
Reduction Reaction ◽  
One Pot ◽  
Capping Agents ◽  
Synthetic Strategy

Highly dispersive carbon-supported octahedral Pt-based catalysts were prepared by an efficient one-pot synthetic strategy without using any bulky capping agents and were demonstrated as promising catalysts for oxygen reduction reaction (ORR).

scholarly journals In Vivo Activity of Oritavancin in Animal Infection Models and Rationale for a New Dosing Regimen in Humans

2012 ◽  
Vol 54 (suppl 3) ◽  
pp. S220-S228 ◽  
Author(s):  
P. G. Ambrose ◽  
G. L. Drusano ◽  
W. A. Craig
Keyword(s):  
Dosing Regimen ◽  
Infection Models ◽  
Animal Infection

scholarly journals Analysis of Endothelial Adherence of Bartonella henselae and Acinetobacter baumannii Using a Dynamic HumanEx VivoInfection Model

2015 ◽  
Vol 84 (3) ◽  
pp. 711-722 ◽  
Author(s):  
Marko Weidensdorfer ◽  
Ju Ik Chae ◽  
Celestine Makobe ◽  
Julia Stahl ◽  
Beate Averhoff ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Pathogenic Bacteria ◽  
Ex Vivo ◽  
Bartonella Henselae ◽  
Dependent Manner ◽  
Content Type ◽  
Human Pathogenic Bacteria ◽  
Infection Models ◽  
Animal Infection

Bacterial adherence determines the virulence of many human-pathogenic bacteria. Experimental approaches elucidating this early infection event in greater detail have been performed using mainly methods of cellular microbiology. However,in vitroinfections of cell monolayers reflect thein vivosituation only partially, and animal infection models are not available for many human-pathogenic bacteria. Therefore,ex vivoinfection of human organs might represent an attractive method to overcome these limitations. We infected whole human umbilical cordsex vivowithBartonella henselaeorAcinetobacter baumanniiunder dynamic flow conditions mimicking thein vivoinfection situation of human endothelium. For this purpose, methods for quantifying endothelium-adherent wild-type and trimeric autotransporter adhesin (TAA)-deficient bacteria were set up. Data revealed that (i)A. baumanniibinds in a TAA-dependent manner to endothelial cells, (ii) this organ infection model led to highly reproducible adherence rates, and furthermore, (iii) this model allowed to dissect the biological function of TAAs in the natural course of human infections. These findings indicate that infection models usingex vivohuman tissue samples (“organ microbiology”) might be a valuable tool in analyzing bacterial pathogenicity with the capacity to replace animal infection models at least partially.

scholarly journals AtypicalSalmonella entericaserovars in murine and human infection models: Is it time to reassess our approach to the study of salmonellosis?

2016 ◽  
Author(s):  
Daniel Hurley ◽  
Maria Hoffmann ◽  
Tim Muruvanda ◽  
Marc W. Allard ◽  
Eric W. Brown ◽  
...  
Keyword(s):  
United States ◽  
Cell Lines ◽  
The United States ◽  
Human Infection ◽  
Raw 264.7 ◽  
Murine Models ◽  
Infection Models ◽  
Foodborne Outbreaks ◽  
Human Infections

AbstractNontyphoidalSalmonellaspecies are globally disseminated pathogens and the predominant cause of gastroenteritis. The pathogenesis of salmonellosis has been extensively studied usingin vivomurine models and cell lines typically challenged withSalmonellaTyphimurium. Although serovars Enteritidis and Typhimurium are responsible for the most of human infections reported to the CDC, several other serovars also contribute to clinical cases of salmonellosis. Despite their epidemiological importance, little is known about their infection phenotypes. Here, we report the virulence characteristics and genomes of 10 atypicalS. entericaserovars linked to multistate foodborne outbreaks in the United States. We show that the murine RAW 264.7 macrophage model of infection is unsuitable for inferring human relevant differences in nontyphoidalSalmonellainfections whereas differentiated human THP-1 macrophages allowed these isolates to be further characterised in a more relevant, human context.

scholarly journals Urea-functionalized amorphous calcium phosphate nanofertilizers: optimizing the synthetic strategy towards environmental sustainability and manufacturing costs

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Francisco J. Carmona ◽  
Gregorio Dal Sasso ◽  
Gloria B. Ramírez-Rodríguez ◽  
Youry Pii ◽  
José Manuel Delgado-López ◽  
...  
Keyword(s):  
Calcium Phosphate ◽  
Environmental Sustainability ◽  
Amorphous Calcium Phosphate ◽  
Cost Effective ◽  
Shoot Biomass ◽  
One Pot ◽  
Synthetic Strategy ◽  
Urea Release ◽  
Use Efficiency

AbstractNanosized fertilizers are the new frontier of nanotechnology towards a sustainable agriculture. Here, an efficient N-nanofertilizer is obtained by post-synthetic modification (PSM) of nitrate-doped amorphous calcium phosphate (ACP) nanoparticles (NPs) with urea. The unwasteful PSM protocol leads to N-payloads as large as 8.1 w/w%, is well replicated by using inexpensive technical-grade reagents for cost-effective up-scaling and moderately favours urea release slowdown. Using the PSM approach, the N amount is ca. 3 times larger than that obtained in an equivalent one-pot synthesis where urea and nitrate are jointly added during the NPs preparation. In vivo tests on cucumber plants in hydroponic conditions show that N-doped ACP NPs, with half absolute N-content than in conventional urea treatment, promote the formation of an equivalent amount of root and shoot biomass, without nitrogen depletion. The high nitrogen use efficiency (up to 69%) and a cost-effective preparation method support the sustainable real usage of N-doped ACP as a nanofertilizer.

A mesoporous tin phosphate–graphene oxide hybrid toward the oxygen reduction reaction

2017 ◽  
Vol 53 (42) ◽  
pp. 5721-5724 ◽  
Author(s):  
Malay Pramanik ◽  
Cuiling Li ◽  
Yusuf Valentino Kaneti ◽  
Yusuke Yamauchi
Keyword(s):  
Graphene Oxide ◽  
Oxygen Reduction Reaction ◽  
Oxygen Reduction ◽  
Reduction Reaction ◽  
Thin Layers ◽  
One Pot ◽  
Synthetic Strategy ◽  
Ordered Mesoporous ◽  
Hexagonally Ordered

We report a one-pot synthetic strategy for the production of an efficient oxygen reduction reaction (ORR) electrocatalyst by the hybridization of hexagonally ordered mesoporous/crystalline tin phosphate (mesoSnPi) nanoflakes with thin layers of graphene oxide (GO).

scholarly journals Evaluation of Possible Correlations between Antifungal Susceptibilities of Filamentous Fungi In Vitro and Antifungal Treatment Outcomes in Animal Infection Models

1998 ◽  
Vol 42 (2) ◽  
pp. 282-288 ◽  
Author(s):  
F. C. Odds ◽  
F. Van Gerven ◽  
A. Espinel-Ingroff ◽  
M. S. Bartlett ◽  
M. A. Ghannoum ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Filamentous Fungi ◽  
Guinea Pigs ◽  
Survival Times ◽  
Pseudallescheria Boydii ◽  
Infection Models ◽  
Animal Infection ◽  
Effective Doses

ABSTRACT Nine isolates of filamentous fungi previously tested in 11 different laboratories for their susceptibilities to amphotericin B and itraconazole in vitro were injected intravenously into mice and guinea pigs, and responses to treatment with both agents were studied. The experiments were done in a single laboratory. Mean survival times, the percentages of animals surviving 12 days after infection, and culture results for samples of deep organs obtained postmortem were used as markers of antifungal efficacy. Because of variations in organism pathogenicity, interpretable test systems in vivo could not be established for Fusarium spp. in mice or guinea pigs or forPseudallescheria boydii in mice, even with the use of immunosuppressive pretreatments. Among the infections that could be evaluated, some degree of response to the corresponding treatment in vivo was seen in animals infected with each of two Rhizopus arrhizus isolates susceptible to amphotericin B at <0.5 μg/ml and Aspergillus spp. isolates susceptible to itraconazole at <1.0 μg/ml. Conversely, no responses were apparent with infecting strains for which MICs were ≥2 μg/ml (amphotericin B) or ≥1 μg/ml (itraconazole). However, the limitations of the intravenous challenge systems studied mean that no firm conclusion relating MICs in vitro to the lowest effective doses in vivo could be drawn.

scholarly journals Improved in vivo PET imaging of the adenosine A2A receptor in the brain using [18F]FLUDA, a deuterated radiotracer with high metabolic stability

2021 ◽  
Author(s):  
Thu Hang Lai ◽  
Magali Toussaint ◽  
Rodrigo Teodoro ◽  
Sladjana Dukić-Stefanović ◽  
Daniel Gündel ◽  
...  
Keyword(s):  
Specific Binding ◽  
Radiochemical Yield ◽  
Toxicity Study ◽  
In Vivo Evaluation ◽  
One Pot ◽  
Specific Binding Ratio ◽  
Mri Studies ◽  
The Brain

Abstract Purpose The adenosine A2A receptor has emerged as a therapeutic target for multiple diseases, and thus the non-invasive imaging of the expression or occupancy of the A2A receptor has potential to contribute to diagnosis and drug development. We aimed at the development of a metabolically stable A2A receptor radiotracer and report herein the preclinical evaluation of [18F]FLUDA, a deuterated isotopologue of [18F]FESCH. Methods [18F]FLUDA was synthesized by a two-step one-pot approach and evaluated in vitro by autoradiographic studies as well as in vivo by metabolism and dynamic PET/MRI studies in mice and piglets under baseline and blocking conditions. A single-dose toxicity study was performed in rats. Results [18F]FLUDA was obtained with a radiochemical yield of 19% and molar activities of 72–180 GBq/μmol. Autoradiography proved A2A receptor–specific accumulation of [18F]FLUDA in the striatum of a mouse and pig brain. In vivo evaluation in mice revealed improved stability of [18F]FLUDA compared to that of [18F]FESCH, resulting in the absence of brain-penetrant radiometabolites. Furthermore, the radiometabolites detected in piglets are expected to have a low tendency for brain penetration. PET/MRI studies confirmed high specific binding of [18F]FLUDA towards striatal A2A receptor with a maximum specific-to-non-specific binding ratio in mice of 8.3. The toxicity study revealed no adverse effects of FLUDA up to 30 μg/kg, ~ 4000-fold the dose applied in human PET studies using [18F]FLUDA. Conclusions The new radiotracer [18F]FLUDA is suitable to detect the availability of the A2A receptor in the brain with high target specificity. It is regarded ready for human application.

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