The Experts below are selected from a list of 258 Experts worldwide ranked by ideXlab platform
Takeshi Nishino - One of the best experts on this subject based on the ideXlab platform.
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extrusion of Penem antibiotics by multicomponent efflux systems mexab oprm mexcd oprj and mexxy oprm of pseudomonas aeruginosa
Antimicrobial Agents and Chemotherapy, 2002Co-Authors: Kiyomi Okamoto, Naomasa Gotoh, Takeshi NishinoAbstract:The high intrinsic Penem resistance of Pseudomonas aeruginosa is due to the interplay among the outer membrane barrier, the active efflux system MexAB-OprM, and AmpC β-lactamase. We studied the roles of two other efflux systems, MexCD-OprJ and MexXY-OprM, in Penem resistance by overexpressing each system in an AmpC- and MexAB-OprM-deficient background and found that MexAB-OprM is the most important among the three efflux systems for extrusion of Penems from the cell interior.
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Extrusion of Penem Antibiotics by Multicomponent Efflux Systems MexAB-OprM, MexCD-OprJ, and MexXY-OprM of Pseudomonas aeruginosa
Antimicrobial agents and chemotherapy, 2002Co-Authors: Kiyomi Okamoto, Naomasa Gotoh, Takeshi NishinoAbstract:The high intrinsic Penem resistance of Pseudomonas aeruginosa is due to the interplay among the outer membrane barrier, the active efflux system MexAB-OprM, and AmpC beta-lactamase. We studied the roles of two other efflux systems, MexCD-OprJ and MexXY-OprM, in Penem resistance by overexpressing each system in an AmpC- and MexAB-OprM-deficient background and found that MexAB-OprM is the most important among the three efflux systems for extrusion of Penems from the cell interior.
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Pseudomonas aeruginosa Reveals High Intrinsic Resistance to Penem Antibiotics: Penem Resistance Mechanisms and Their Interplay
Antimicrobial agents and chemotherapy, 2001Co-Authors: Kiyomi Okamoto, Naomasa Gotoh, Takeshi NishinoAbstract:Pseudomonas aeruginosa exhibits high intrinsic resistance to Penem antibiotics such as faroPenem, ritiPenem, AMA3176, suloPenem, Sch29482, and Sch34343. To investigate the mechanisms contributing to Penem resistance, we used the laboratory strain PAO1 to construct a series of isogenic mutants with an impaired multidrug efflux system MexAB-OprM and/or impaired chromosomal AmpC beta-lactamase. The outer membrane barrier of PAO1 was partially eliminated by inducing the expression of the plasmid-encoded Escherichia coli major porin OmpF. Susceptibility tests using the mutants and the OmpF expression plasmid showed that MexAB-OprM and the outer membrane barrier, but not AmpC beta-lactamase, are the main mechanisms involved in the high intrinsic Penem resistance of PAO1. However, reducing the high intrinsic Penem resistance of PAO1 to the same level as that of Penem-susceptible gram-negative bacteria such as E. coli required the loss of either both MexAB-OprM and AmpC beta-lactamase or both MexAB-OprM and the outer membrane barrier. Competition experiments for penicillin-binding proteins (PBPs) revealed that the affinity of PBP 1b and PBP 2 for faroPenem were about 1.8- and 1.5-fold lower, than the respective affinity for imiPenem. Loss of the outer membrane barrier, MexAB, and AmpC beta-lactamase increased the susceptibility of PAO1 to almost all Penems tested compared to the susceptibility of the AmpC-deficient PAO1 mutants to imiPenem. Thus, it is suggested that the high intrinsic Penem resistance of P. aeruginosa is generated from the interplay among the outer membrane barrier, the active efflux system, and AmpC beta-lactamase but not from the lower affinity of PBPs for Penems.
Kiyomi Okamoto - One of the best experts on this subject based on the ideXlab platform.
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extrusion of Penem antibiotics by multicomponent efflux systems mexab oprm mexcd oprj and mexxy oprm of pseudomonas aeruginosa
Antimicrobial Agents and Chemotherapy, 2002Co-Authors: Kiyomi Okamoto, Naomasa Gotoh, Takeshi NishinoAbstract:The high intrinsic Penem resistance of Pseudomonas aeruginosa is due to the interplay among the outer membrane barrier, the active efflux system MexAB-OprM, and AmpC β-lactamase. We studied the roles of two other efflux systems, MexCD-OprJ and MexXY-OprM, in Penem resistance by overexpressing each system in an AmpC- and MexAB-OprM-deficient background and found that MexAB-OprM is the most important among the three efflux systems for extrusion of Penems from the cell interior.
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Extrusion of Penem Antibiotics by Multicomponent Efflux Systems MexAB-OprM, MexCD-OprJ, and MexXY-OprM of Pseudomonas aeruginosa
Antimicrobial agents and chemotherapy, 2002Co-Authors: Kiyomi Okamoto, Naomasa Gotoh, Takeshi NishinoAbstract:The high intrinsic Penem resistance of Pseudomonas aeruginosa is due to the interplay among the outer membrane barrier, the active efflux system MexAB-OprM, and AmpC beta-lactamase. We studied the roles of two other efflux systems, MexCD-OprJ and MexXY-OprM, in Penem resistance by overexpressing each system in an AmpC- and MexAB-OprM-deficient background and found that MexAB-OprM is the most important among the three efflux systems for extrusion of Penems from the cell interior.
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Pseudomonas aeruginosa Reveals High Intrinsic Resistance to Penem Antibiotics: Penem Resistance Mechanisms and Their Interplay
Antimicrobial agents and chemotherapy, 2001Co-Authors: Kiyomi Okamoto, Naomasa Gotoh, Takeshi NishinoAbstract:Pseudomonas aeruginosa exhibits high intrinsic resistance to Penem antibiotics such as faroPenem, ritiPenem, AMA3176, suloPenem, Sch29482, and Sch34343. To investigate the mechanisms contributing to Penem resistance, we used the laboratory strain PAO1 to construct a series of isogenic mutants with an impaired multidrug efflux system MexAB-OprM and/or impaired chromosomal AmpC beta-lactamase. The outer membrane barrier of PAO1 was partially eliminated by inducing the expression of the plasmid-encoded Escherichia coli major porin OmpF. Susceptibility tests using the mutants and the OmpF expression plasmid showed that MexAB-OprM and the outer membrane barrier, but not AmpC beta-lactamase, are the main mechanisms involved in the high intrinsic Penem resistance of PAO1. However, reducing the high intrinsic Penem resistance of PAO1 to the same level as that of Penem-susceptible gram-negative bacteria such as E. coli required the loss of either both MexAB-OprM and AmpC beta-lactamase or both MexAB-OprM and the outer membrane barrier. Competition experiments for penicillin-binding proteins (PBPs) revealed that the affinity of PBP 1b and PBP 2 for faroPenem were about 1.8- and 1.5-fold lower, than the respective affinity for imiPenem. Loss of the outer membrane barrier, MexAB, and AmpC beta-lactamase increased the susceptibility of PAO1 to almost all Penems tested compared to the susceptibility of the AmpC-deficient PAO1 mutants to imiPenem. Thus, it is suggested that the high intrinsic Penem resistance of P. aeruginosa is generated from the interplay among the outer membrane barrier, the active efflux system, and AmpC beta-lactamase but not from the lower affinity of PBPs for Penems.
Maria Altamura - One of the best experts on this subject based on the ideXlab platform.
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MEN 10700, a new Penem antibiotic: in vitro antibacterial activity on clinical isolates.
Chemotherapy, 2002Co-Authors: Lucio Ferrari, Maria Altamura, Massimo De Luca, Tomaso CerutiAbstract:MEN 10700 is a new broad-spectrum Penem, currently in preclinical development. In the present study, the activity of MEN 10700 was compared to that of imiPenem, meroPenem, cefotaxime, ampicillin/sulba
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X-ray Structures of Three Penem Antibiotics: Molecular Mechanical and Dynamic Aspects
Structural Chemistry, 1999Co-Authors: Paolo Dapporto, Maria Altamura, Paola Paoli, Patrizia Rossi, Enzo PerrottaAbstract:The structures of three β-lactam Penem antibiotics—i.e. the sodium[5R-[5α,6α(R*)]]-6-(1-hydroxyethyl)-7-oxo-3-[[(1-pyrrolidinylthioxomethyl)thio]methyl]-4-thia-1-azabicyclo[3.2.0] hept-2-ene-2-carboxylate (compound 1 ), the [5R-[3(S*),5α,6α(R*)]]-3-[[2-(aminocarbonyl)-1-pyrrolidinyl] methyl]-6-(1-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (compound 2 ), and the [5R-[5α,6α(R*)]]-3-[[(2-amino-2-oxoethyl) methylamino]methyl]-6-(1-hydroxyethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (compound 3 )—have been determined by X-ray analyses. In the crystal lattice two conformational isomers of 1 are present, which differ from each other in the spatial arrangement of the dithiocarbamate chain. Compounds 2 and 3 are in zwitterionic form, being the hydrogen of the carboxylic acid moved to the amino nitrogen of the chain at C2. This hydrogen atom, in both molecules, forms intramolecular hydrogen bonds with an oxygen atom of the carboxylate moiety and with the oxygen atom of the amido group of the side chain. The 3D structures of 1 , 2 , and 3 have been compared with those of previously reported β-lactam Penem antibiotics. Particularly, the Woodward parameter and the Cohen distance, which are considered important in determining the antibiotic activity, have been discussed. Least-squares minimizations (RMS) of the distances between nuclei of selected pairs of atoms defining the pharmacological pattern have been performed, comparing five common antibiotics (imiPenem, ritiPenem, cephaloridine, amoxycillin, and benzylpenicillin) with our compounds. Finally, molecular dynamics calculations have been carried out on the three Penem antibiotics at different temperatures. The conformational behavior of the hydroxyethyl chain, the carboxylate group, and the chain at C2 is discussed by considering the variation of some selected dihedral angles.
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Synthesis of New 2-Thiomethyl Penem Derivatives
Synthetic Communications, 1995Co-Authors: Danilo Giannotti, Maria AltamuraAbstract:Abstract New Penem thiolesters (4-5) were synthesized and 5 was hydrolyzed. 2-mercaptomethyl Penem7 is formedin situand transformed into Penem monothiocarbamates9 and10.
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Structure-activity relationship of new 2-substituted Penem antibiotics.
The Journal of antibiotics, 1995Co-Authors: Roberta Fontana, Federico Arcamone, Maria Altamura, Giuseppe Cornaglia, Grazia Angela Morandotti, R. Sperning, Sebastiano Valisena, Giuseppe SattaAbstract:The antibacterial activities of three new Penems with 4-hydroxyprolinamide, I-prolinamide and N-methyl-N-2-propionamide substituents, respectively, in position 2 and of their stereoisomers were examined against Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Escherichia coli and Pseudomonas aeruginosa. All substituents conferred a broad antibacterial spectrum on the Penem moiety. Changes in stereoisomerism selectively improved the activity against E. coli, S. aureus or enterococci. The structure-activity relationships of each compound were discussed in relation to minimum inhibitory concentrations, penicillin-binding protein (PBP) affinity and outer membrane permeability coefficient in E. coli. In this microorganism, PBP 2 was the target for all compounds. Changes in stereoisomerism influenced the affinity for PBPs 1A/B and 2. All antibiotics easily permeated the outer membrane of E. coli and, within each group of compounds, the penetration rate correlated with the antibacterial activity.
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Synthesis and antibacterial activity of men 10700, a new Penem antibiotic
Bioorganic & Medicinal Chemistry Letters, 1995Co-Authors: Maria Altamura, Enzo Perrotta, Piero Sbraci, Vittorio Pestellini, Arcamone Federico, Giuseppe Satta, Grazia Angela Morandotti, Giuseppe Cascio, Roberta SperrungAbstract:The new Penem antibiotic Men 10700 (3), bearing an amino acid derived amide as C-2 side chain, was synthesized. Men 10700 exhibited high potency and a broad spectrum of activity against Gram positive and Gram negative microorganisms.
Naomasa Gotoh - One of the best experts on this subject based on the ideXlab platform.
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extrusion of Penem antibiotics by multicomponent efflux systems mexab oprm mexcd oprj and mexxy oprm of pseudomonas aeruginosa
Antimicrobial Agents and Chemotherapy, 2002Co-Authors: Kiyomi Okamoto, Naomasa Gotoh, Takeshi NishinoAbstract:The high intrinsic Penem resistance of Pseudomonas aeruginosa is due to the interplay among the outer membrane barrier, the active efflux system MexAB-OprM, and AmpC β-lactamase. We studied the roles of two other efflux systems, MexCD-OprJ and MexXY-OprM, in Penem resistance by overexpressing each system in an AmpC- and MexAB-OprM-deficient background and found that MexAB-OprM is the most important among the three efflux systems for extrusion of Penems from the cell interior.
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Extrusion of Penem Antibiotics by Multicomponent Efflux Systems MexAB-OprM, MexCD-OprJ, and MexXY-OprM of Pseudomonas aeruginosa
Antimicrobial agents and chemotherapy, 2002Co-Authors: Kiyomi Okamoto, Naomasa Gotoh, Takeshi NishinoAbstract:The high intrinsic Penem resistance of Pseudomonas aeruginosa is due to the interplay among the outer membrane barrier, the active efflux system MexAB-OprM, and AmpC beta-lactamase. We studied the roles of two other efflux systems, MexCD-OprJ and MexXY-OprM, in Penem resistance by overexpressing each system in an AmpC- and MexAB-OprM-deficient background and found that MexAB-OprM is the most important among the three efflux systems for extrusion of Penems from the cell interior.
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Pseudomonas aeruginosa Reveals High Intrinsic Resistance to Penem Antibiotics: Penem Resistance Mechanisms and Their Interplay
Antimicrobial agents and chemotherapy, 2001Co-Authors: Kiyomi Okamoto, Naomasa Gotoh, Takeshi NishinoAbstract:Pseudomonas aeruginosa exhibits high intrinsic resistance to Penem antibiotics such as faroPenem, ritiPenem, AMA3176, suloPenem, Sch29482, and Sch34343. To investigate the mechanisms contributing to Penem resistance, we used the laboratory strain PAO1 to construct a series of isogenic mutants with an impaired multidrug efflux system MexAB-OprM and/or impaired chromosomal AmpC beta-lactamase. The outer membrane barrier of PAO1 was partially eliminated by inducing the expression of the plasmid-encoded Escherichia coli major porin OmpF. Susceptibility tests using the mutants and the OmpF expression plasmid showed that MexAB-OprM and the outer membrane barrier, but not AmpC beta-lactamase, are the main mechanisms involved in the high intrinsic Penem resistance of PAO1. However, reducing the high intrinsic Penem resistance of PAO1 to the same level as that of Penem-susceptible gram-negative bacteria such as E. coli required the loss of either both MexAB-OprM and AmpC beta-lactamase or both MexAB-OprM and the outer membrane barrier. Competition experiments for penicillin-binding proteins (PBPs) revealed that the affinity of PBP 1b and PBP 2 for faroPenem were about 1.8- and 1.5-fold lower, than the respective affinity for imiPenem. Loss of the outer membrane barrier, MexAB, and AmpC beta-lactamase increased the susceptibility of PAO1 to almost all Penems tested compared to the susceptibility of the AmpC-deficient PAO1 mutants to imiPenem. Thus, it is suggested that the high intrinsic Penem resistance of P. aeruginosa is generated from the interplay among the outer membrane barrier, the active efflux system, and AmpC beta-lactamase but not from the lower affinity of PBPs for Penems.
Robert A. Bonomo - One of the best experts on this subject based on the ideXlab platform.
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Kinetic and Structural Characterization of the Interaction of 6-Methylidene Penem 2 with the β-Lactamase from Mycobacterium tuberculosis.
Biochemistry, 2015Co-Authors: Saugata Hazra, Robert A. Bonomo, Sebastian G Kurz, Kerstin A. Wolff, Liem Nguyen, John S. BlanchardAbstract:Mycobacterium tuberculosis is intrinsically resistant to most β-lactam antibiotics because of the constitutive expression of the blaC-encoded β-lactamase. This enzyme has extremely high activity against penicillins and cephalosporins, but weaker activity against carbaPenems. The enzyme can be inhibited by clavulanate, avibactam, and boronic acids. In this study, we investigated the ability of 6-methylidene β-lactams to inhibit BlaC. One such compound, Penem 2, inhibited BlaC more than 70 times more efficiently than clavulanate. The compound forms a covalent complex with BlaC as shown by mass spectrometry. Crystallization of the complex revealed that the bound inhibitor was covalently attached via the Ser70 active site residue and that the covalently, acylated form of the inhibitor had undergone additional chemistry yielding a 4,7-thiazepine ring in place of the β-lactam and a thiazapyroline ring generated as a result of β-lactam ring opening. The stereochemistry of the product of the 7-endo-trig cyclization was the opposite of that observed previously for class A and D β-lactamases. Addition of Penem 2 greatly synergized the antibacterial properties of both ampicillin and meroPenem against a growing culture of M. tuberculosis. Strikingly, Penem 2 alone showed significant growth inhibition, suggesting that in addition to its capability of efficiently inhibiting BlaC, it also inhibited the peptidoglycan cross-linking transpeptidases.
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Penem and penam sulfones and their reaction mechanisms.
2013Co-Authors: Priyaranjan Pattanaik, Christopher R. Bethel, Anjaneyulu Sheri, John D. Buynak, Robert A. Bonomo, Focco Van Den AkkerAbstract:(A) Chemical structures of Penem and penam sulfone compounds. (B) proposed inhibition mechanism by a Penem 1 (based on Knox’s work and others) [10], [11]; carbon atoms labeled with * are the stereo centers; (C) proposed reaction mechanism of SA1-204.
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Penem 1 in SHV-1 active site. (
2013Co-Authors: Priyaranjan Pattanaik, Christopher R. Bethel, Anjaneyulu Sheri, John D. Buynak, Robert A. Bonomo, Focco Van Den AkkerAbstract:A) Stereo view of Penem 1 interactions in SHV-1 active site. Hydrogen bonds are shown as dashed lines. (B) Stereo view of superpositioning of Penem 1:SHV-1 (black) and Penem 2:SHV-1 structures (grey). (C) Stereo view of superpositioning of Penem 1:SHV-1 (black) and Penem 2:GC1 β-lactamase (grey).
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Minimum Inhibitory Concentrations (MICs) of Piperacillin (Pip) in Combination with 4 µg/ml Tazobactam (Tazo), and Penem 1.
2013Co-Authors: Priyaranjan Pattanaik, Christopher R. Bethel, Anjaneyulu Sheri, John D. Buynak, Robert A. Bonomo, Focco Van Den AkkerAbstract:Minimum Inhibitory Concentrations (MICs) of Piperacillin (Pip) in Combination with 4 µg/ml Tazobactam (Tazo), and Penem 1.
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Structures of SHV-1 β-Lactamase with Penem and Penam Sulfone Inhibitors That Form Cyclic Intermediates Stabilized by Carbonyl Conjugation
PloS one, 2012Co-Authors: Priyaranjan Pattanaik, Christopher R. Bethel, Anjaneyulu Sheri, John D. Buynak, Robert A. Bonomo, Focco Van Den AkkerAbstract:Bacterial β-lactamase enzymes are in large part responsible for the decreased ability of β-lactam antibiotics to combat infections. The inability to overcome β-lactamase mediated resistance spurred the development of inhibitors with Penems and penam sulfones being amongst the most potent and broad spectrum mechanism-based inactivators. These inhibitors form covalent, "suicide-type" inhibitory intermediates that are attached to the catalytic S70 residue. To further probe the details of the mechanism of β-lactamase inhibition by these novel compounds, we determined the crystal structures of SHV-1 bound with Penem 1, and penam sulfones SA1-204 and SA3-53. Comparison with each other and with previously determined crystal structures of members of these classes of inhibitors suggests that the final conformation of the covalent adduct can vary greatly amongst the complex structures. In contrast, a common theme of carbonyl conjugation as a mechanism to avoid deacylation emerges despite that the Penem and penam sulfone inhibitors form different types of intermediates. The detailed insights gained from this study could be used to further improve new mechanism-based inhibitors of these common class A serine β-lactamases.
