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Stephan Köhler - One of the best experts on this subject based on the ideXlab platform.
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Brucella suis carbonic anhydrases and their inhibitors: Towards alternative antibiotics?
Journal of Enzyme Inhibition and Medicinal Chemistry, 2017Co-Authors: Stephan Köhler, Safia Ouahrani-bettache, Jean-yves WinumAbstract:Carbonic anhydrases have started to emerge as new potential antibacterial targets for several pathogens. Two β-carbonic anhydrases, denominated bsCA I and bsCA II, have been isolated and characterized from the bacterial pathogen Brucella suis, the causative agent of brucellosis or Malta fever. These enzymes have been investigated in detail and a wide range of classical aromatic and heteroaromatic sulfonamides as well as carbohydrate-based compounds have been found to inhibit selectively and efficiently Brucella suis carbonic anhydrases. Inhibition of these metalloenzymes constitutes a novel approach for the potential development of new anti-Brucella agents. This review aims at discussing the recent literature on this topic.
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N-glycosyl-N-hydroxysulfamides as potent inhibitors of Brucella suis carbonic anhydrases
Journal of enzyme inhibition and medicinal chemistry, 2015Co-Authors: Joanna Ombouma, Stephan Köhler, Claudiu T. Supuran, Daniela Vullo, Pascal Dumy, Jean-yves WinumAbstract:We investigated a series of N-hydroxysulfamides obtained by Ferrier sulfamidoglycosylation for the inhibition of two bacterial carbonic anhydrases (CAs, EC 4.2.1.1) present in the pathogen Brucella suis. bsCA I was moderately inhibited by these compounds with inhibition constants ranging between 522 and 958 nM and no notable differences of activity between the acetylated or the corresponding deacetylated derivatives. The compounds incorporating two trans-acetates and the corresponding deprotected ones were the most effective inhibitors in the series. bsCA II was better inhibited, with inhibition constants ranging between 59.8 and 799 nM. The acetylated derivatives were generally better bsCA II inhibitors compared to the corresponding deacetylated compounds. Although these compounds were not highly isoform-selective CA inhibitors (CAIs) for the bacterial over the human CA isoforms, some of them possess inhibition profiles that make them interesting leads for obtaining better and more isoform-selective CAIs targeting bacterial enzymes.
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Inhibition of β-carbonic anhydrases from Brucella suis with C-cinnamoyl glycosides incorporating the phenol moiety.
Journal of enzyme inhibition and medicinal chemistry, 2015Co-Authors: Leonardo E. Riafrecha, Safia Ouahrani-bettache, Stephan Köhler, Jean-yves Winum, Claudiu T. Supuran, Daniela Vullo, Pascal Dumy, Pedro A. ColinasAbstract:A small series of C-glycosides containing the phenol moiety was tested for the inhibition of the β-class carbonic anhydrases (βCAs, EC 4.2.1.1) from Brucella suis. Many compounds showed activities in the micromolar or submicromolar range and excellent selectivity for pathogen CAs over human isozymes. Glycosides incorporating the 3-hydroxyphenyl moiety showed the best inhibition profile, and therefore this functionality represents lead for the development of novel anti-infectives with a new mechanism of action.
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Cloning, Characterization, and Inhibition Studies of a β-Carbonic Anhydrase from Brucella suis
Journal of medicinal chemistry, 2010Co-Authors: Pascale Joseph, Safia Ouahrani-bettache, Stephan Köhler, Jeanlouis Montero, Daniela Vullo, François Turtaut, Isao Nishimori, Tomoko Minakuchi, Andrea Scozzafava, Jean-yves WinumAbstract:A β-carbonic anhydrase (CA, EC 4.2.1.1) from the bacterial pathogen Brucella suis, bsCA 1, has been cloned, purified, and characterized kinetically. bsCA 1 has appreciable activity as catalyst for the hydration of CO2 to bicarbonate, with a kcat of 6.4 × 105 s−1 and kcat/Km of 3.9 × 107 M−1·s−1. A panel of 38 sulfonamides and one sulfamate have been investigated for inhibition of this new β-CA. All types of activities have been detected, with KIs in the range of 17 nM to 5.87 μM. The best bsCA 1 inhibitors were ethoxzolamide (17 nM), celecoxib (18 nM), dorzolamide (21 nM), valdecoxib, and sulpiride (19 nM). Whether bsCA 1 inhibitors may have application in the fight against brucellosis, an endemic disease and the major bacterial zoonosis, producing debilitating infection in humans and animals, warrants further studies.
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Cloning, characterization, and inhibition studies of a beta-carbonic anhydrase from Brucella suis.
Journal of Medicinal Chemistry, 2010Co-Authors: Pascale Joseph, Safia Ouahrani-bettache, Stephan Köhler, Jeanlouis Montero, Daniela Vullo, François Turtaut, Isao Nishimori, Tomoko Minakuchi, Andrea Scozzafava, Jean-yves WinumAbstract:A beta-carbonic anhydrase (CA, EC 4.2.1.1) from the bacterial pathogen Brucella suis, bsCA 1, has been cloned, purified, and characterized kinetically. bsCA 1 has appreciable activity as catalyst for the hydration of CO(2) to bicarbonate, with a k(cat) of 6.4 x 10(5) s(-1) and k(cat)/K(m) of 3.9 x 10(7) M(-1).s(-1). A panel of 38 sulfonamides and one sulfamate have been investigated for inhibition of this new beta-CA. All types of activities have been detected, with K(I)s in the range of 17 nM to 5.87 microM. The best bsCA 1 inhibitors were ethoxzolamide (17 nM), celecoxib (18 nM), dorzolamide (21 nM), valdecoxib, and sulpiride (19 nM). Whether bsCA 1 inhibitors may have application in the fight against brucellosis, an endemic disease and the major bacterial zoonosis, producing debilitating infection in humans and animals, warrants further studies.
Jean-yves Winum - One of the best experts on this subject based on the ideXlab platform.
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Brucella suis carbonic anhydrases and their inhibitors: Towards alternative antibiotics?
Journal of Enzyme Inhibition and Medicinal Chemistry, 2017Co-Authors: Stephan Köhler, Safia Ouahrani-bettache, Jean-yves WinumAbstract:Carbonic anhydrases have started to emerge as new potential antibacterial targets for several pathogens. Two β-carbonic anhydrases, denominated bsCA I and bsCA II, have been isolated and characterized from the bacterial pathogen Brucella suis, the causative agent of brucellosis or Malta fever. These enzymes have been investigated in detail and a wide range of classical aromatic and heteroaromatic sulfonamides as well as carbohydrate-based compounds have been found to inhibit selectively and efficiently Brucella suis carbonic anhydrases. Inhibition of these metalloenzymes constitutes a novel approach for the potential development of new anti-Brucella agents. This review aims at discussing the recent literature on this topic.
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N-glycosyl-N-hydroxysulfamides as potent inhibitors of Brucella suis carbonic anhydrases
Journal of enzyme inhibition and medicinal chemistry, 2015Co-Authors: Joanna Ombouma, Stephan Köhler, Claudiu T. Supuran, Daniela Vullo, Pascal Dumy, Jean-yves WinumAbstract:We investigated a series of N-hydroxysulfamides obtained by Ferrier sulfamidoglycosylation for the inhibition of two bacterial carbonic anhydrases (CAs, EC 4.2.1.1) present in the pathogen Brucella suis. bsCA I was moderately inhibited by these compounds with inhibition constants ranging between 522 and 958 nM and no notable differences of activity between the acetylated or the corresponding deacetylated derivatives. The compounds incorporating two trans-acetates and the corresponding deprotected ones were the most effective inhibitors in the series. bsCA II was better inhibited, with inhibition constants ranging between 59.8 and 799 nM. The acetylated derivatives were generally better bsCA II inhibitors compared to the corresponding deacetylated compounds. Although these compounds were not highly isoform-selective CA inhibitors (CAIs) for the bacterial over the human CA isoforms, some of them possess inhibition profiles that make them interesting leads for obtaining better and more isoform-selective CAIs targeting bacterial enzymes.
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Inhibition of β-carbonic anhydrases from Brucella suis with C-cinnamoyl glycosides incorporating the phenol moiety.
Journal of enzyme inhibition and medicinal chemistry, 2015Co-Authors: Leonardo E. Riafrecha, Safia Ouahrani-bettache, Stephan Köhler, Jean-yves Winum, Claudiu T. Supuran, Daniela Vullo, Pascal Dumy, Pedro A. ColinasAbstract:A small series of C-glycosides containing the phenol moiety was tested for the inhibition of the β-class carbonic anhydrases (βCAs, EC 4.2.1.1) from Brucella suis. Many compounds showed activities in the micromolar or submicromolar range and excellent selectivity for pathogen CAs over human isozymes. Glycosides incorporating the 3-hydroxyphenyl moiety showed the best inhibition profile, and therefore this functionality represents lead for the development of novel anti-infectives with a new mechanism of action.
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Cloning, Characterization, and Inhibition Studies of a β-Carbonic Anhydrase from Brucella suis
Journal of medicinal chemistry, 2010Co-Authors: Pascale Joseph, Safia Ouahrani-bettache, Stephan Köhler, Jeanlouis Montero, Daniela Vullo, François Turtaut, Isao Nishimori, Tomoko Minakuchi, Andrea Scozzafava, Jean-yves WinumAbstract:A β-carbonic anhydrase (CA, EC 4.2.1.1) from the bacterial pathogen Brucella suis, bsCA 1, has been cloned, purified, and characterized kinetically. bsCA 1 has appreciable activity as catalyst for the hydration of CO2 to bicarbonate, with a kcat of 6.4 × 105 s−1 and kcat/Km of 3.9 × 107 M−1·s−1. A panel of 38 sulfonamides and one sulfamate have been investigated for inhibition of this new β-CA. All types of activities have been detected, with KIs in the range of 17 nM to 5.87 μM. The best bsCA 1 inhibitors were ethoxzolamide (17 nM), celecoxib (18 nM), dorzolamide (21 nM), valdecoxib, and sulpiride (19 nM). Whether bsCA 1 inhibitors may have application in the fight against brucellosis, an endemic disease and the major bacterial zoonosis, producing debilitating infection in humans and animals, warrants further studies.
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Cloning, characterization, and inhibition studies of a beta-carbonic anhydrase from Brucella suis.
Journal of Medicinal Chemistry, 2010Co-Authors: Pascale Joseph, Safia Ouahrani-bettache, Stephan Köhler, Jeanlouis Montero, Daniela Vullo, François Turtaut, Isao Nishimori, Tomoko Minakuchi, Andrea Scozzafava, Jean-yves WinumAbstract:A beta-carbonic anhydrase (CA, EC 4.2.1.1) from the bacterial pathogen Brucella suis, bsCA 1, has been cloned, purified, and characterized kinetically. bsCA 1 has appreciable activity as catalyst for the hydration of CO(2) to bicarbonate, with a k(cat) of 6.4 x 10(5) s(-1) and k(cat)/K(m) of 3.9 x 10(7) M(-1).s(-1). A panel of 38 sulfonamides and one sulfamate have been investigated for inhibition of this new beta-CA. All types of activities have been detected, with K(I)s in the range of 17 nM to 5.87 microM. The best bsCA 1 inhibitors were ethoxzolamide (17 nM), celecoxib (18 nM), dorzolamide (21 nM), valdecoxib, and sulpiride (19 nM). Whether bsCA 1 inhibitors may have application in the fight against brucellosis, an endemic disease and the major bacterial zoonosis, producing debilitating infection in humans and animals, warrants further studies.
Zeljko Cvetnic - One of the best experts on this subject based on the ideXlab platform.
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characterisation of Brucella suis isolates from southeast europe by multi locus variable number tandem repeat analysis
Veterinary Microbiology, 2015Co-Authors: Sanja Duvnjak, Irena Reil, Ivana Racic, Silvio Spicic, Maja Zdelartuk, Zeljko CvetnicAbstract:Porcine brucellosis is a common bacterial zoonosis which can cause significant financial losses. Its diverse and often complicated factors have hampered efforts to control disease spread. The aim of the study was to assess the epidemiological situation of porcine brucellosis primarily in Croatia and its relationship to genotypes present in other, mostly European countries. One hundred and seven Brucella suis strains isolated from swine, hares, cattle, humans, wild hares, a wild boar and a mare originating mainly from Croatia (112), but also a few from Slovenia, Bosnia and Herzegovina, Serbia and Macedonia (15) were tested using classical microbiological testing, Bruce-ladder, RFLP, Multiplex-suis and genotyped using multi-locus variable-number tandem repeat analysis (MLVA). We determined 43 Brucella suis genotypes. Strains were grouped according to phylogenetic and geographic relationships, revealing both regional specificity and uniqueness and suggesting possible sources and modes of spread among animals. Our study also confirmed problems with Bruce19 locus that may hinder comparisons of new types with those in the international database. Forty-one novel genotypes were identified and deposited into the international database. Our study supports the idea of wild animals as a source of disease in domestic animals and also gives evidence to hypothesis of cross-border animal trafficking between former Yugoslavian countries. It also highlights the need to expand such research across more of southeast Europe, especially to countries with poorer social and economical situation in order to prevent a realistic outbreak and for better understanding of the biology of this pathogen.
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Comparison of Multiple-Locus Variable-Number Tandem-Repeat Analysis with Other PCR-Based Methods for Typing Brucella suis Isolates
Journal of clinical microbiology, 2007Co-Authors: David García-yoldi, Clara M Marin, Philippe Le Flèche, María Jesús De Miguel, Pilar M. Muñoz, José M. Blasco, Zeljko Cvetnic, Gilles Vergnaud, Ignacio López-goñiAbstract:Multiple-locus variable-number tandem-repeat analysis (MLVA), multiplex PCR, and PCR-restriction fragment length polymorphism analysis were compared for typing Brucella suis isolates. A perfect concordance was obtained among these molecular assays. However, MLVA was the only method to demonstrate brucellosis outbreaks and to confirm that wildlife is a reservoir for zoonotic brucellosis.
Hai Jiang - One of the best experts on this subject based on the ideXlab platform.
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Molecular Investigation of the Transmission Pattern of Brucella suis 3 From Inner Mongolia, China.
Frontiers in veterinary science, 2018Co-Authors: Zhiguo Liu, Bu Yun Cui, Hong Yan Zhao, Dong Ri Piao, Li-jun Wang, Miao Wang, Rihong Liu, Hai JiangAbstract:Brucellosis is an endemic disease in China affecting both humans and livestock. The aim of the present study was to analyze two Brucella strains isolated from sheep spleens from Ulanqab in Inner Mongolia, China using classical and molecular typing techniques. The two strains were identified as Brucella suis biovar 3 and were closely related to isolates previously obtained from two different hosts (human and swine) in Guangxi Province. Our results suggest that B. suis can be directly or indirectly transferred from swine to sheep, which act as reservoirs for B. suis infection and later transmitted to humans. Multiple locus variable-number tandem repeat analysis (MLVA) is a useful tool for tracing the geographical origin of brucellosis infections and elucidating its transmission patterns.
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Table_2_Molecular Investigation of the Transmission Pattern of Brucella suis 3 From Inner Mongolia, China.docx
2018Co-Authors: Zhiguo Liu, Bu Yun Cui, Hong Yan Zhao, Dong Ri Piao, Li-jun Wang, Miao Wang, Rihong Liu, Hai JiangAbstract:Brucellosis is an endemic disease in China affecting both humans and livestock. The aim of the present study was to analyze two Brucella strains isolated from sheep spleens from Ulanqab in Inner Mongolia, China using classical and molecular typing techniques. The two strains were identified as Brucella suis biovar 3 and were closely related to isolates previously obtained from two different hosts (human and swine) in Guangxi Province. Our results suggest that B. suis can be directly or indirectly transferred from swine to sheep, which act as reservoirs for B. suis infection and later transmitted to humans. Multiple locus variable-number tandem repeat analysis (MLVA) is a useful tool for tracing the geographical origin of brucellosis infections and elucidating its transmission patterns.
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Table_1_Molecular Investigation of the Transmission Pattern of Brucella suis 3 From Inner Mongolia, China.XLSX
2018Co-Authors: Zhiguo Liu, Bu Yun Cui, Hong Yan Zhao, Dong Ri Piao, Li-jun Wang, Miao Wang, Rihong Liu, Hai JiangAbstract:Brucellosis is an endemic disease in China affecting both humans and livestock. The aim of the present study was to analyze two Brucella strains isolated from sheep spleens from Ulanqab in Inner Mongolia, China using classical and molecular typing techniques. The two strains were identified as Brucella suis biovar 3 and were closely related to isolates previously obtained from two different hosts (human and swine) in Guangxi Province. Our results suggest that B. suis can be directly or indirectly transferred from swine to sheep, which act as reservoirs for B. suis infection and later transmitted to humans. Multiple locus variable-number tandem repeat analysis (MLVA) is a useful tool for tracing the geographical origin of brucellosis infections and elucidating its transmission patterns.
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Comparative genomic analysis between newly sequenced Brucella suis Vaccine Strain S2 and the Virulent Brucella suis Strain 1330
BMC genomics, 2016Co-Authors: Hai Jiang, Li-li Tian, Jing Li Kang, Wen Zhang, Qi ZhongAbstract:Brucellosis is a bacterial disease caused by Brucella infection. In the late fifties, Brucella suis vaccine strain S2 with reduced virulence was obtained by serial transfer of a virulent B. suis biovar 1 strain in China. It has been widely used for vaccination in China since 1971. Until now, the mechanisms underlie virulence attenuation of S2 are still unknown. In this paper, the whole genome sequencing of S2 was carried out by Illumina Hiseq2000 sequencing method. We further performed the comparative genomic analysis to find out the differences between S2 and the virulent Brucella suis strain 1330. We found premature stops in outer membrane autotransporter omaA and eryD genes. Single mutations were found in phosphatidylcholine synthase, phosphorglucosamine mutase, pyruvate kinase and FliF, which have been reported to be related to the virulence of Brucella or other bacteria. Of the other different proteins between S2 and 1330, such as Omp2b, periplasmic sugar-binding protein, and oligopeptide ABC transporter, no definitive implications related to bacterial virulence were found, which await further investigation. The data presented here provided the rational basis for designing Brucella vaccines that could be used in other strains.
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Molecular typing of Brucella suis collected from 1960s to 2010s in China by MLVA and PFGE.
Biomedical and environmental sciences : BES, 2013Co-Authors: Bu Yun Cui, Hai Chen, Jing Diao Chen, Hong Yan Zhao, Dong Ri Piao, Hai Jiang, Li Zhang, Xu TangAbstract:Brucellosis is a bacterial anthropozoonosis usually caused by Brucella abortus, Brucella melitensis, Brucella suis and Brucella canis. Brucella suis, the causative agent of swine brucellosis, is classified into five biovars and preferentially infects different animal hosts [1] .
Safia Ouahrani-bettache - One of the best experts on this subject based on the ideXlab platform.
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Brucella suis carbonic anhydrases and their inhibitors: Towards alternative antibiotics?
Journal of Enzyme Inhibition and Medicinal Chemistry, 2017Co-Authors: Stephan Köhler, Safia Ouahrani-bettache, Jean-yves WinumAbstract:Carbonic anhydrases have started to emerge as new potential antibacterial targets for several pathogens. Two β-carbonic anhydrases, denominated bsCA I and bsCA II, have been isolated and characterized from the bacterial pathogen Brucella suis, the causative agent of brucellosis or Malta fever. These enzymes have been investigated in detail and a wide range of classical aromatic and heteroaromatic sulfonamides as well as carbohydrate-based compounds have been found to inhibit selectively and efficiently Brucella suis carbonic anhydrases. Inhibition of these metalloenzymes constitutes a novel approach for the potential development of new anti-Brucella agents. This review aims at discussing the recent literature on this topic.
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Inhibition of β-carbonic anhydrases from Brucella suis with C-cinnamoyl glycosides incorporating the phenol moiety.
Journal of enzyme inhibition and medicinal chemistry, 2015Co-Authors: Leonardo E. Riafrecha, Safia Ouahrani-bettache, Stephan Köhler, Jean-yves Winum, Claudiu T. Supuran, Daniela Vullo, Pascal Dumy, Pedro A. ColinasAbstract:A small series of C-glycosides containing the phenol moiety was tested for the inhibition of the β-class carbonic anhydrases (βCAs, EC 4.2.1.1) from Brucella suis. Many compounds showed activities in the micromolar or submicromolar range and excellent selectivity for pathogen CAs over human isozymes. Glycosides incorporating the 3-hydroxyphenyl moiety showed the best inhibition profile, and therefore this functionality represents lead for the development of novel anti-infectives with a new mechanism of action.
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Cloning, Characterization, and Inhibition Studies of a β-Carbonic Anhydrase from Brucella suis
Journal of medicinal chemistry, 2010Co-Authors: Pascale Joseph, Safia Ouahrani-bettache, Stephan Köhler, Jeanlouis Montero, Daniela Vullo, François Turtaut, Isao Nishimori, Tomoko Minakuchi, Andrea Scozzafava, Jean-yves WinumAbstract:A β-carbonic anhydrase (CA, EC 4.2.1.1) from the bacterial pathogen Brucella suis, bsCA 1, has been cloned, purified, and characterized kinetically. bsCA 1 has appreciable activity as catalyst for the hydration of CO2 to bicarbonate, with a kcat of 6.4 × 105 s−1 and kcat/Km of 3.9 × 107 M−1·s−1. A panel of 38 sulfonamides and one sulfamate have been investigated for inhibition of this new β-CA. All types of activities have been detected, with KIs in the range of 17 nM to 5.87 μM. The best bsCA 1 inhibitors were ethoxzolamide (17 nM), celecoxib (18 nM), dorzolamide (21 nM), valdecoxib, and sulpiride (19 nM). Whether bsCA 1 inhibitors may have application in the fight against brucellosis, an endemic disease and the major bacterial zoonosis, producing debilitating infection in humans and animals, warrants further studies.
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Cloning, characterization, and inhibition studies of a beta-carbonic anhydrase from Brucella suis.
Journal of Medicinal Chemistry, 2010Co-Authors: Pascale Joseph, Safia Ouahrani-bettache, Stephan Köhler, Jeanlouis Montero, Daniela Vullo, François Turtaut, Isao Nishimori, Tomoko Minakuchi, Andrea Scozzafava, Jean-yves WinumAbstract:A beta-carbonic anhydrase (CA, EC 4.2.1.1) from the bacterial pathogen Brucella suis, bsCA 1, has been cloned, purified, and characterized kinetically. bsCA 1 has appreciable activity as catalyst for the hydration of CO(2) to bicarbonate, with a k(cat) of 6.4 x 10(5) s(-1) and k(cat)/K(m) of 3.9 x 10(7) M(-1).s(-1). A panel of 38 sulfonamides and one sulfamate have been investigated for inhibition of this new beta-CA. All types of activities have been detected, with K(I)s in the range of 17 nM to 5.87 microM. The best bsCA 1 inhibitors were ethoxzolamide (17 nM), celecoxib (18 nM), dorzolamide (21 nM), valdecoxib, and sulpiride (19 nM). Whether bsCA 1 inhibitors may have application in the fight against brucellosis, an endemic disease and the major bacterial zoonosis, producing debilitating infection in humans and animals, warrants further studies.
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The Brucella suis virB operon is induced intracellularly in macrophages
Proceedings of the National Academy of Sciences, 2002Co-Authors: Maria Laura Boschiroli, A. Allardet-servent, C. Cazevieille, Safia Ouahrani-bettache, Jean-pierre Liautard, Gisele Bourg, Vincent Foulongne, Sylvie Michaux-charachon, Marc Ramuz, David O'callaghanAbstract:A type IV secretion system similar to the VirB system of the phytopathogen Agrobacterium tumefaciens is essential for the intracellular survival and multiplication of the mammalian pathogen Brucella. Reverse transcriptase-PCR showed that the 12 genes encoding the Brucella suis VirB system form an operon. Semiquantitative measurements of virB mRNA levels by slot blotting showed that transcription of the virB operon, but not the flanking genes, is regulated by environmental factors in vitro. Flow cytometry used to measure green fluorescent protein expression from the virB promoter confirmed the data from slot blots. Fluorescence-activated cell sorter analysis and fluorescence microscopy showed that the virB promoter is induced in macrophages within 3 h after infection. Induction only occurred once the bacteria were inside the cells, and phagosome acidification was shown to be the major signal inducing intracellular expression. Because phagosome acidification is essential for the intracellular multiplication of Brucella, we suggest that it is the signal that triggers the secretion of unknown effector molecules. These effector molecules play a role in the remodeling of the phagosome to create the unique intracellular compartment in which Brucella replicates.
