Hoffmann M

References (17)

Title : Photoswitchable Pseudoirreversible Butyrylcholinesterase Inhibitors Allow Optical Control of Inhibition in Vitro and Enable Restoration of Cognition in an Alzheimer's Disease Mouse Model upon Irradiation - Scheiner_2022_J.Am.Chem.Soc__
Author(s) : Scheiner M , Sink A , Hoffmann M , Vrigneau C , Endres E , Carles A , Sotriffer C , Maurice T , Decker M
Ref : Journal of the American Chemical Society , : , 2022
Abstract : To develop tools to investigate the biological functions of butyrylcholinesterase (BChE) and the mechanisms by which BChE affects Alzheimer's disease (AD), we synthesized several selective, nanomolar active, pseudoirreversible photoswitchable BChE inhibitors. The compounds were able to specifically influence different kinetic parameters of the inhibition process by light. For one compound, a 10-fold difference in the IC(50)-values (44.6 nM cis, 424 nM trans) in vitro was translated to an "all or nothing" response with complete recovery in a murine cognition-deficit AD model at dosages as low as 0.3 mg/kg.
ESTHER : Scheiner_2022_J.Am.Chem.Soc__
PubMedSearch : Scheiner_2022_J.Am.Chem.Soc__
PubMedID: 35138833

Title : Selective Pseudo-irreversible Butyrylcholinesterase Inhibitors Transferring Antioxidant Moieties to the Enzyme Show Pronounced Neuroprotective Efficacy In Vitro and In Vivo in an Alzheimer's Disease Mouse Model - Scheiner_2021_J.Med.Chem_64_9302
Author(s) : Scheiner M , Hoffmann M , He F , Poeta E , Chatonnet A , Monti B , Maurice T , Decker M
Ref : Journal of Medicinal Chemistry , 64(13): :9302 , 2021
Abstract : A series of multitarget-directed ligands (MTDLs) was designed by functionalizing a pseudo-irreversible butyrylcholinesterase (BChE) inhibitor. The obtained hybrids were investigated in vitro regarding their hBChE and hAChE inhibition, their enzyme kinetics, and their antioxidant physicochemical properties (DPPH, ORAC, metal chelating). In addition, in vitro assays were applied to investigate antioxidant effects using murine hippocampal HT22 cells and immunomodulatory effects on the murine microglial N9 cell line. The MTDLs retained their antioxidative properties compared to the parent antioxidant-moieties in vitro and the inhibition of hBChE was maintained in the submicromolar range. Representative compounds were tested in a pharmacological Alzheimer's disease (AD) mouse model and demonstrated very high efficacy at doses as low as 0.1 mg/kg. The most promising compound was also tested in BChE(-/-) mice and showed reduced efficacy. In vivo neuroprotection by BChE inhibition can be effectively enhanced by incorporation of structurally diverse antioxidant moieties.
ESTHER : Scheiner_2021_J.Med.Chem_64_9302
PubMedSearch : Scheiner_2021_J.Med.Chem_64_9302
PubMedID: 34152756

Title : Synthesis and Initial Characterization of a Selective, Pseudo-irreversible Inhibitor of Human Butyrylcholinesterase as PET Tracer - Gentzsch_2021_ChemMedChem__
Author(s) : Gentzsch C , Hoffmann M , Ohshima Y , Nose N , Chen X , Higuchi T , Decker M
Ref : ChemMedChem , : , 2021
Abstract : The enzyme butyrylcholinesterase (BChE) represents a promising target for imaging probes to potentially enable early diagnosis of neurodegenerative diseases like Alzheimer's disease (AD) and to monitor disease progression in some forms of cancer. In this study, we present the design, facile synthesis, invitro and preliminary ex vivo and invivo evaluation of a morpholine-based, selective inhibitor of human BChE as a positron emission tomography (PET) tracer with a pseudo-irreversible binding mode. We demonstrate a novel protecting group strategy for (18) F radiolabeling of carbamate precursors and show that the inhibitory potency as well as kinetic properties of our unlabeled reference compound were retained in comparison to the parent compound. In particular, the prolonged duration of enzyme inhibition of such a morpholinocarbamate motivated us to design a PET tracer, possibly enabling a precise mapping of BChE distribution.
ESTHER : Gentzsch_2021_ChemMedChem__
PubMedSearch : Gentzsch_2021_ChemMedChem__
PubMedID: 33645891

Title : Sterubin: Enantioresolution and Configurational Stability, Enantiomeric Purity in Nature, and Neuroprotective Activity in Vitro and in Vivo - Hofmann_2020_Chemistry_26_7299
Author(s) : Hofmann J , Fayez S , Scheiner M , Hoffmann M , Oerter S , Appelt-Menzel A , Maher P , Maurice T , Bringmann G , Decker M
Ref : Chemistry , 26 :7299 , 2020
Abstract : Alzheimer's disease (AD) is a neurological disorder with still no preventive or curative treatment. Flavonoids are phytochemicals with potential therapeutic value. Previous studies described the flavanone sterubin isolated from the Californian plant Eriodictyon californicum as a potent neuroprotectant in several in vitro assays. Herein, the resolution of synthetic racemic sterubin (1) into its two enantiomers, (R)-1 and (S)-1, is described, which has been performed on a chiral chromatographic phase, and their stereochemical assignment online by HPLC-ECD coupling. (R)-1 and (S)-1 showed comparable neuroprotection in vitro with no significant differences. While the pure stereoisomers were configurationally stable in methanol, fast racemization was observed in the presence of culture medium. We also established the occurrence of extracted sterubin as its pure (S)-enantiomer. Moreover, the activity of sterubin (1) was investigated for the first time in vivo, in an AD mouse model. Sterubin (1) showed a significant positive impact on short- and long-term memory at low dosages.
ESTHER : Hofmann_2020_Chemistry_26_7299
PubMedSearch : Hofmann_2020_Chemistry_26_7299
PubMedID: 32358806

Title : 7-O-Esters of taxifolin with pronounced and overadditive effects in neuroprotection, anti-neuroinflammation, and amelioration of short-term memory impairment in vivo - Gunesch_2020_Redox.Biol_29_101378
Author(s) : Gunesch S , Hoffmann M , Kiermeier C , Fischer W , Pinto AFM , Maurice T , Maher P , Decker M
Ref : Redox Biol , 29 :101378 , 2020
Abstract : Alzheimer's disease (AD) is a multifactorial disease and the most common form of dementia. There are no treatments to cure, prevent or slow down the progression of the disease. Natural products hold considerable interest for the development of preventive neuroprotectants to treat neurodegenerative disorders like AD, due to their low toxicity and general beneficial effects on human health with their anti-inflammatory and antioxidant features. In this work we describe regioselective synthesis of 7-O-ester hybrids of the flavonoid taxifolin with the phenolic acids cinnamic and ferulic acid, namely 7-O-cinnamoyltaxifolin and 7-O-feruloyltaxifolin. The compounds show pronounced overadditive neuroprotective effects against oxytosis, ferroptosis and ATP depletion in the murine hippocampal neuron HT22cell model. Furthermore, 7-O-cinnamoyltaxifolin and 7-O-feruloyltaxifolin reduced LPS-induced neuroinflammation in BV-2 microglia cells as assessed by effects on the levels of NO, IL6 and TNFalpha. In all in vitro assays the 7-O-esters of taxifolin and ferulic or cinnamic acid showed strong overadditive activity, significantly exceeding the effects of the individual components and the equimolar mixtures thereof, which were almost inactive in all of the assays at the tested concentrations. In vivo studies confirmed this overadditive effect. Treatment of an AD mouse model based on the injection of oligomerized Abeta25-35 peptide into the brain to cause neurotoxicity and subsequently memory deficits with 7-O-cinnamoyltaxifolin or 7-O-feruloyltaxifolin resulted in improved performance in an assay for short-term memory as compared to vehicle and mice treated with the respective equimolar mixtures. These results highlight the benefits of natural product hybrids as a novel compound class with potential use for drug discovery in neurodegenerative diseases due to their pharmacological profile that is distinct from the individual natural components.
ESTHER : Gunesch_2020_Redox.Biol_29_101378
PubMedSearch : Gunesch_2020_Redox.Biol_29_101378
PubMedID: 31926632

Title : Polymorphisms in dipeptidyl peptidase 4 reduce host cell entry of Middle East respiratory syndrome coronavirus - Kleine-Weber_2020_Emerg.Microbes.Infect_9_155
Author(s) : Kleine-Weber H , Schroeder S , Kruger N , Prokscha A , Naim HY , Muller MA , Drosten C , Pohlmann S , Hoffmann M
Ref : Emerg Microbes Infect , 9 :155 , 2020
Abstract : Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) causes a severe respiratory disease in humans. The MERS-CoV spike (S) glycoprotein mediates viral entry into target cells. For this, MERS-CoV S engages the host cell protein dipeptidyl peptidase 4 (DPP4, CD26) and the interface between MERS-CoV S and DPP4 has been resolved on the atomic level. Here, we asked whether naturally-occurring polymorphisms in DPP4, that alter amino acid residues required for MERS-CoV S binding, influence cellular entry of MERS-CoV. By screening of public databases, we identified fourteen such polymorphisms. Introduction of the respective mutations into DPP4 revealed that all except one (Delta346-348) were compatible with robust DPP4 expression. Four polymorphisms (K267E, K267N, A291P and Delta346-348) strongly reduced binding of MERS-CoV S to DPP4 and S protein-driven host cell entry, as determined using soluble S protein and S protein bearing rhabdoviral vectors, respectively. Two polymorphisms (K267E and A291P) were analyzed in the context of authentic MERS-CoV and were found to attenuate viral replication. Collectively, we identified naturally-occurring polymorphisms in DPP4 that negatively impact cellular entry of MERS-CoV and might thus modulate MERS development in infected patients.
ESTHER : Kleine-Weber_2020_Emerg.Microbes.Infect_9_155
PubMedSearch : Kleine-Weber_2020_Emerg.Microbes.Infect_9_155
PubMedID: 31964246

Title : N-1,2,3-triazole-isatin derivatives for cholinesterase and beta-amyloid aggregation inhibition: A comprehensive bioassay study - Marques_2020_Bioorg.Chem_98_103753
Author(s) : Marques CS , Lopez O , Bagetta D , Carreiro EP , Petralla S , Bartolini M , Hoffmann M , Alcaro S , Monti B , Bolognesi ML , Decker M , Fernandez-Bolanos JG , Burke AJ
Ref : Bioorg Chem , 98 :103753 , 2020
Abstract : Our goal was the evaluation of a series of N-1,2,3-triazole-isatin derivatives for multi-target activity which included cholinesterase (ChE) inhibition and beta-amyloid (Abeta) peptide anti-aggregation. The compounds have shown considerable promise as butyrylcholinesterase (BuChE) inhibitors. Although the inhibition of eel acetylcholinesterase (eeAChE) was weak, the inhibitions against equine BuChE (eqBuChE) and human BuChE (hBuChE) were more significant with a best inhibition against eqBuChE of 0.46 muM. In some cases, these molecules gave better inhibitions for hBuChE than eqBuChE. For greater insights into their mode of action, molecular docking studies were carried out, followed by STD-NMR validation. In addition, some of these compounds showed weak Abeta anti-aggregation activity. Hepatotoxicity studies showed that they were non-hepatoxic and neurotoxicity studies using neurite outgrowth experiments led to the conclusion that these compounds are only weakly neurotoxic.
ESTHER : Marques_2020_Bioorg.Chem_98_103753
PubMedSearch : Marques_2020_Bioorg.Chem_98_103753
PubMedID: 32200328

Title : Dual-Acting Cholinesterase-Human Cannabinoid Receptor 2 Ligands Show Pronounced Neuroprotection in Vitro and Overadditive and Disease-Modifying Neuroprotective Effects in Vivo - Scheiner_2019_J.Med.Chem_62_9078
Author(s) : Scheiner M , Dolles D , Gunesch S , Hoffmann M , Nabissi M , Marinelli O , Naldi M , Bartolini M , Petralla S , Poeta E , Monti B , Falkeis C , Vieth M , Hubner H , Gmeiner P , Maitra R , Maurice T , Decker M
Ref : Journal of Medicinal Chemistry , 62 :9078 , 2019
Abstract : We have designed and synthesized a series of 14 hybrid molecules out of the cholinesterase (ChE) inhibitor tacrine and a benzimidazole-based human cannabinoid receptor subtype 2 (hCB2R) agonist and investigated them in vitro and in vivo. The compounds are potent ChE inhibitors, and for the most promising hybrids, the mechanism of human acetylcholinesterase (hAChE) inhibition as well as their ability to interfere with AChE-induced aggregation of beta-amyloid (Abeta), and Abeta self-aggregation was assessed. All hybrids were evaluated for affinity and selectivity for hCB1R and hCB2R. To ensure that the hybrids retained their agonist character, the expression of cAMP-regulated genes was quantified, and potency and efficacy were determined. Additionally, the effects of the hybrids on microglia activation and neuroprotection on HT-22 cells were investigated. The most promising in vitro hybrids showed pronounced neuroprotection in an Alzheimer's mouse model at low dosage (0.1 mg/kg, i.p.), lacking hepatotoxicity even at high dose (3 mg/kg, i.p.).
ESTHER : Scheiner_2019_J.Med.Chem_62_9078
PubMedSearch : Scheiner_2019_J.Med.Chem_62_9078
PubMedID: 31609608

Title : Highly Selective Butyrylcholinesterase Inhibitors with Tunable Duration of Action by Chemical Modification of Transferable Carbamate Units Exhibit Pronounced Neuroprotective Effect in an Alzheimer's Disease Mouse Model - Hoffmann_2019_J.Med.Chem_62_9116
Author(s) : Hoffmann M , Stiller C , Endres E , Scheiner M , Gunesch S , Sotriffer C , Maurice T , Decker M
Ref : Journal of Medicinal Chemistry , 62 :9116 , 2019
Abstract : In this study, the carbamate structure of pseudo-irreversible butyrylcholinesterase (BChE) inhibitors was optimized with regard to a longer binding to the enzyme. A set of compounds bearing different heterocycles (e.g., morpholine, tetrahydroisoquinoline, benzimidazole, piperidine) and alkylene spacers (2 to 10 methylene groups between carbamate and heterocycle) in the carbamate residue was synthesized and characterized in vitro for their binding affinity, binding kinetics, and carbamate hydrolysis. These novel BChE inhibitors are highly selective for hBChE over human acetycholinesterase (hAChE), yielding short-, medium-, and long-acting nanomolar hBChE inhibitors (with a half-life of the carbamoylated enzyme ranging from 1 to 28 h). The inhibitors show neuroprotective properties in a murine hippocampal cell line and a pharmacological mouse model of Alzheimer's disease (AD), suggesting a significant benefit of BChE inhibition for a disease-modifying treatment of AD.
ESTHER : Hoffmann_2019_J.Med.Chem_62_9116
PubMedSearch : Hoffmann_2019_J.Med.Chem_62_9116
PubMedID: 31609115

Title : Mutations in the Spike Protein of Middle East Respiratory Syndrome Coronavirus Transmitted in Korea Increase Resistance to Antibody-Mediated Neutralization - Kleine-Weber_2019_J.Virol_93_
Author(s) : Kleine-Weber H , Elzayat MT , Wang L , Graham BS , Muller MA , Drosten C , Pohlmann S , Hoffmann M
Ref : J Virol , 93 : , 2019
Abstract : Middle East respiratory syndrome coronavirus (MERS-CoV) poses a threat to public health. The virus is endemic in the Middle East but can be transmitted to other countries by travel activity. The introduction of MERS-CoV into the Republic of Korea by an infected traveler resulted in a hospital outbreak of MERS that entailed 186 cases and 38 deaths. The MERS-CoV spike (S) protein binds to the cellular protein DPP4 via its receptor binding domain (RBD) and mediates viral entry into target cells. During the MERS outbreak in Korea, emergence and spread of viral variants that harbored mutations in the RBD, D510G and I529T, was observed. Counterintuitively, these mutations were found to reduce DPP4 binding and viral entry into target cells. In this study, we investigated whether they also exerted proviral effects. We confirm that changes D510G and I529T reduce S protein binding to DPP4 but show that this reduction only translates into diminished viral entry when expression of DPP4 on target cells is low. Neither mutation modulated S protein binding to sialic acids, S protein activation by host cell proteases, or inhibition of S protein-driven entry by interferon-induced transmembrane proteins. In contrast, changes D510G and I529T increased resistance of S protein-driven entry to neutralization by monoclonal antibodies and sera from MERS patients. These findings indicate that MERS-CoV variants with reduced neutralization sensitivity were transmitted during the Korean outbreak and that the responsible mutations were compatible with robust infection of cells expressing high levels of DPP4.IMPORTANCE MERS-CoV has pandemic potential, and it is important to identify mutations in viral proteins that might augment viral spread. In the course of a large hospital outbreak of MERS in the Republic of Korea in 2015, the spread of a viral variant that contained mutations in the viral spike protein was observed. These mutations were found to reduce receptor binding and viral infectivity. However, it remained unclear whether they also exerted proviral effects. We demonstrate that these mutations reduce sensitivity to antibody-mediated neutralization and are compatible with robust infection of target cells expressing large amounts of the viral receptor DPP4.
ESTHER : Kleine-Weber_2019_J.Virol_93_
PubMedSearch : Kleine-Weber_2019_J.Virol_93_
PubMedID: 30404801

Title : Structure-Activity Relationships and Computational Investigations into the Development of Potent and Balanced Dual-Acting Butyrylcholinesterase Inhibitors and Human Cannabinoid Receptor 2 Ligands with Pro-Cognitive in Vivo Profiles - Dolles_2018_J.Med.Chem_61_1646
Author(s) : Dolles D , Hoffmann M , Gunesch S , Marinelli O , Moller J , Santoni G , Chatonnet A , Lohse MJ , Wittmann HJ , Strasser A , Nabissi M , Maurice T , Decker M
Ref : Journal of Medicinal Chemistry , 61 :1646 , 2018
Abstract : The enzyme butyrylcholinesterase (BChE) and the human cannabinoid receptor 2 (hCB2R) represent promising targets for pharmacotherapy in the later stages of Alzheimer's disease. We merged pharmacophores for both targets into small benzimidazole-based molecules, investigated SARs, and identified several dual-acting ligands with a balanced affinity/inhibitory activity and an excellent selectivity over both hCB1R and hAChE. A homology model for the hCB2R was developed based on the hCB1R crystal structure and used for molecular dynamics studies to investigate binding modes. In vitro studies proved hCB2R agonism. Unwanted mu-opioid receptor affinity could be designed out. One well-balanced dual-acting and selective hBChE inhibitor/hCB2R agonist showed superior in vivo activity over the lead CB2 agonist with regards to cognition improvement. The data shows the possibility to combine a small molecule with selective and balanced GPCR-activity/enzyme inhibition and in vivo activity for the therapy of AD and may help to rationalize the development of other dual-acting ligands.
ESTHER : Dolles_2018_J.Med.Chem_61_1646
PubMedSearch : Dolles_2018_J.Med.Chem_61_1646
PubMedID: 29400965

Title : Comparative genomic analysis and virulence differences in closely related salmonella enterica serotype heidelberg isolates from humans, retail meats, and animals - Hoffmann_2014_Genome.Biol.Evol_6_1046
Author(s) : Hoffmann M , Zhao S , Pettengill J , Luo Y , Monday SR , Abbott J , Ayers SL , Cinar HN , Muruvanda T , Li C , Allard MW , Whichard J , Meng J , Brown EW , McDermott PF
Ref : Genome Biol Evol , 6 :1046 , 2014
Abstract : Salmonella enterica subsp. enterica serovar Heidelberg (S. Heidelberg) is one of the top serovars causing human salmonellosis. Recently, an antibiotic-resistant strain of this serovar was implicated in a large 2011 multistate outbreak resulting from consumption of contaminated ground turkey that involved 136 confirmed cases, with one death. In this study, we assessed the evolutionary diversity of 44 S. Heidelberg isolates using whole-genome sequencing (WGS) generated by the 454 GS FLX (Roche) platform. The isolates, including 30 with nearly indistinguishable (one band difference) Xbal pulsed-field gel electrophoresis patterns (JF6X01.0032, JF6X01.0058), were collected from various sources between 1982 and 2011 and included nine isolates associated with the 2011 outbreak. Additionally, we determined the complete sequence for the chromosome and three plasmids from a clinical isolate associated with the 2011 outbreak using the Pacific Biosciences (PacBio) system. Using single-nucleotide polymorphism (SNP) analyses, we were able to distinguish highly clonal isolates, including strains isolated at different times in the same year. The isolates from the recent 2011 outbreak clustered together with a mean SNP variation of only 17 SNPs. The S. Heidelberg isolates carried a variety of phages, such as prophage P22, P4, lambda-like prophage Gifsy-2, and the P2-like phage which carries the sopE1 gene, virulence genes including 62 pathogenicity, and 13 fimbrial markers and resistance plasmids of the incompatibility (Inc)I1, IncA/C, and IncHI2 groups. Twenty-one strains contained an IncX plasmid carrying a type IV secretion system. On the basis of the recent and historical isolates used in this study, our results demonstrated that, in addition to providing detailed genetic information for the isolates, WGS can identify SNP targets that can be utilized for differentiating highly clonal S. Heidelberg isolates.
ESTHER : Hoffmann_2014_Genome.Biol.Evol_6_1046
PubMedSearch : Hoffmann_2014_Genome.Biol.Evol_6_1046
PubMedID: 24732280

Title : Genome Sequences of Salmonella enterica Serovar Heidelberg Isolates Isolated in the United States from a Multistate Outbreak of Human Salmonella Infections - Hoffmann_2013_Genome.Announc_1_e00004
Author(s) : Hoffmann M , Luo Y , Lafon PC , Timme R , Allard MW , McDermott PF , Brown EW , Zhao S
Ref : Genome Announc , 1 : , 2013
Abstract : Salmonella enterica is recognized as one of the most common bacterial agents of foodborne illness. We report draft genomes of four Salmonella serovar Heidelberg isolates associated with the recent multistate outbreak of human Salmonella Heidelberg infections linked to kosher broiled chicken livers in the United States in 2011. Isolates 2011K-1259 and 2011K-1232 were recovered from humans, whereas 2011K-1724 and 2011K-1726 were isolated from chicken liver. Whole genome sequence analysis of these isolates provides a tool for studying the short-term evolution of these epidemic clones and can be used for characterizing potentially new virulence factors.
ESTHER : Hoffmann_2013_Genome.Announc_1_e00004
PubMedSearch : Hoffmann_2013_Genome.Announc_1_e00004
PubMedID: 23405335
Gene_locus related to this paper: salty-STY1441

Title : Complete Genome Sequence of a Multidrug-Resistant Salmonella enterica Serovar Typhimurium var. 5- Strain Isolated from Chicken Breast - Hoffmann_2013_Genome.Announc_1_e01068
Author(s) : Hoffmann M , Muruvanda T , Allard MW , Korlach J , Roberts RJ , Timme R , Payne J , McDermott PF , Evans P , Meng J , Brown EW , Zhao S
Ref : Genome Announc , 1 : , 2013
Abstract : Salmonella enterica subsp. enterica serovar Typhimurium is a leading cause of salmonellosis. Here, we report a closed genome sequence, including sequences of 3 plasmids, of Salmonella serovar Typhimurium var. 5- CFSAN001921 (National Antimicrobial Resistance Monitoring System [NARMS] strain ID N30688), which was isolated from chicken breast meat and shows resistance to 10 different antimicrobials. Whole-genome and plasmid sequence analyses of this isolate will help enhance our understanding of this pathogenic multidrug-resistant serovar.
ESTHER : Hoffmann_2013_Genome.Announc_1_e01068
PubMedSearch : Hoffmann_2013_Genome.Announc_1_e01068
PubMedID: 24356834

Title : Biochemical and biophysical analysis of a chiral PqsD inhibitor revealing tight-binding behavior and enantiomers with contrary thermodynamic signatures - Storz_2013_ACS.Chem.Biol_8_2794
Author(s) : Storz MP , Brengel C , Weidel E , Hoffmann M , Hollemeyer K , Steinbach A , Muller R , Empting M , Hartmann RW
Ref : ACS Chemical Biology , 8 :2794 , 2013
Abstract : Antivirulence strategies addressing bacterial pathogenicity without exhibiting growth inhibition effects represent a novel approach to overcome today's crisis in antibiotic development. In recent studies, we examined various inhibitors of PqsD, an enzyme involved in formation of Pseudomonas aeruginosa cell-to-cell signaling molecules, and observed desired cellular effects for 2-nitrophenyl derivatives. Herein, we investigated the binding characteristics of this interesting compound class using several biochemical and biophysical methods. The inhibitors showed time-dependent activity, tight-binding behavior, and interactions with the catalytic center. Furthermore, isothermal titration calorimetry (ITC) experiments with separated enantiomers revealed contrary thermodynamic signatures showing either enthalpy- or entropy-driven affinity. A combination of site-directed mutagenesis and thermodynamic profiling was used to identify key residues involved in inhibitor binding. This information allowed the proposal of experimentally confirmed docking poses. Although originally designed as transition state analogs, our results suggest an altered position for both enantiomers. Interestingly, the main difference between stereoisomers was found in the orientation of the hydroxyl group at the stereogenic center. The predicted binding modes are in accordance with experimental data and, thus, allow future structure-guided optimization.
ESTHER : Storz_2013_ACS.Chem.Biol_8_2794
PubMedSearch : Storz_2013_ACS.Chem.Biol_8_2794
PubMedID: 24099650

Title : Genome sequences of five Salmonella enterica serovar Heidelberg isolates associated with a 2011 multistate outbreak in the United States - Hoffmann_2012_J.Bacteriol_194_3274
Author(s) : Hoffmann M , Zhao S , Luo Y , Li C , Folster JP , Whichard J , Allard MW , Brown EW , McDermott PF
Ref : Journal of Bacteriology , 194 :3274 , 2012
Abstract : Salmonella enterica serovar Heidelberg has caused numerous outbreaks in humans. Here, we report draft genomes of five isolates of serovar Heidelberg associated with the recent (2011) multistate outbreak linked to ground turkey in the United States. Isolates 2011K-1110 and 2011K-1132 were recovered from humans, while isolates 2011K-1138, 2011K-1224, and 2011K-1225 were recovered from ground turkey. Whole-genome sequence analysis of these isolates provides a tool for studying the short-term evolution of these epidemic clones.
ESTHER : Hoffmann_2012_J.Bacteriol_194_3274
PubMedSearch : Hoffmann_2012_J.Bacteriol_194_3274
PubMedID: 22628505
Gene_locus related to this paper: salty-STY1441 , salty-YFBB

Title : Vibrio caribbeanicus sp. nov., isolated from the marine sponge Scleritoderma cyanea - Hoffmann_2012_Int.J.Syst.Evol.Microbiol_62_1736
Author(s) : Hoffmann M , Monday SR , Allard MW , Strain EA , Whittaker P , Naum M , McCarthy PJ , Lopez JV , Fischer M , Brown EW
Ref : Int J Syst Evol Microbiol , 62 :1736 , 2012
Abstract : A Gram-negative, oxidase-positive, catalase-negative, facultatively anaerobic, motile, curved rod-shaped bacterium, strain N384(T), was isolated from a marine sponge (Scleritoderma cyanea; phylum Porifera) collected from a depth of 795 feet (242 m) off the west coast of Curacao. On the basis of 16S rRNA gene sequencing, strain N384(T) was shown to belong to the genus Vibrio, most closely related to Vibrio brasiliensis LMG 20546(T) (98.8% similarity), Vibrio nigripulchritudo ATCC 27043(T) (98.5%), Vibrio tubiashii ATCC 19109(T) (98.6%) and V. sinaloensis DSM 21326(T) (98.2%). The DNA G+C content of strain N384(T) was 41.6 mol%. An analysis of concatenated sequences of five genes (gyrB, rpoA, pyrH, mreB and ftsZ; 4068 bp) demonstrated a clear separation between strain N384(T) and its closest neighbours and clustered strain N384(T) into the 'Orientalis' clade of vibrios. Phenotypically, the novel species belonged to the arginine dihydrolase-positive, lysine decarboxylase- and ornithine decarboxylase-negative (A+/L-/O-) cluster. The novel species was also differentiated on the basis of fatty acid composition, specifically that the proportions of iso-C(13:0), iso-C(15:0), C(15:0), iso-C(16:0), C(16:0), iso-C(17:0), C(17:1)omega8c and C(17:0) were significantly different from those found in V. brasiliensis and V. sinaloensis. The results of DNA-DNA hybridization, average nucleotide identity and physiological and biochemical tests further allowed differentiation of this strain from other described species of the genus Vibrio. Collectively, these findings confirm that strain N384(T) represents a novel Vibrio species, for which the name Vibrio caribbeanicus sp. nov. is proposed, with the type strain N384(T) ( = ATCC BAA-2122(T) = DSM 23640(T)).
ESTHER : Hoffmann_2012_Int.J.Syst.Evol.Microbiol_62_1736
PubMedSearch : Hoffmann_2012_Int.J.Syst.Evol.Microbiol_62_1736
PubMedID: 21930677
Gene_locus related to this paper: 9vibr-e3blh9 , 9vibr-e8m7m8 , vibor-c9qmm3 , vibsl-b7vj94 , vibor-c9qjb6 , 9vibr-e3bpr1 , 9vibr-e8lzq9 , 9vibr-e8m9i4 , 9vibr-f9rtw3 , 9vibr-f9rx95 , 9vibr-f9t4v1 , 9vibr-f9tu24 , vibor-c9qfa1 , 9vibr-e3bex7 , 9vibr-e8lx06 , 9vibr-e8lyu5 , 9vibr-e8mag8 , 9vibr-u4ij97 , vibsp-f9shk7 , 9vibr-f9t646 , 9vibr-f9rl84 , 9vibr-e8lnb6 , vibor-c9qmw4 , 9vibr-e8m7u5 , 9vibr-f9rwr5 , 9vibr-f9tk00 , 9vibr-e8m290 , 9vibr-i1dgf8 , 9vibr-f9rmi2 , 9vibr-f9ry64 , 9vibr-e8lsk0 , vibor-c9qih4 , vibsp-f9sg12