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David Crich - One of the best experts on this subject based on the ideXlab platform.
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effects of the 1 n 4 amino 2s hydroxybutyryl and 6 n 2 hydroxyethyl substituents on ribosomal selectivity cochleotoxicity and antibacterial activity in the sisomicin class of Aminoglycoside Antibiotics
ACS Infectious Diseases, 2018Co-Authors: Amr Sonousi, Vikram A Sarpe, Margarita Brilkova, Jochen Schacht, Andrea Vasella, Erik C Bottger, David CrichAbstract:Syntheses of the 6′-N-(2-hydroxyethyl) and 1-N-(4-amino-2S-hydroxybutyryl) derivatives of the 4,6-Aminoglycoside sisomicin and that of the doubly modified 1-N-(4-amino-2S-hydroxybutyryl)-6′-N-(2-hydroxyethyl) derivative known as plazomicin are reported together with their antibacterial and antiribosomal activities and selectivities. The 6′-N-(2-hydroxyethyl) modification results in a moderate increase in prokaryotic/eukaryotic ribosomal selectivity, whereas the 1-N-(4-amino-2S-hydroxybutyryl) modification has the opposite effect. When combined in plazomicin, the effects of the two groups on ribosomal selectivity cancel each other out, leading to the prediction that plazomicin will exhibit ototoxicity comparable to those of the parent and the current clinical Aminoglycoside Antibiotics gentamicin and tobramycin, as borne out by ex vivo studies with mouse cochlear explants. The 6′-N-(2-hydroxyethyl) modification restores antibacterial activity in the presence of the AAC(6′) Aminoglycoside-modifying enzymes,...
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Effects of the 1‑N‑(4-Amino‑2S‑hydroxybutyryl) and 6′‑N‑(2-Hydroxyethyl) Substituents on Ribosomal Selectivity, Cochleotoxicity, and Antibacterial Activity in the Sisomicin Class of Aminoglycoside Antibiotics
2018Co-Authors: Amr Sonousi, Vikram A Sarpe, Margarita Brilkova, Jochen Schacht, Andrea Vasella, Erik C. Böttger, David CrichAbstract:Syntheses of the 6′-N-(2-hydroxyethyl) and 1-N-(4-amino-2S-hydroxybutyryl) derivatives of the 4,6-Aminoglycoside sisomicin and that of the doubly modified 1-N-(4-amino-2S-hydroxybutyryl)-6′-N-(2-hydroxyethyl) derivative known as plazomicin are reported together with their antibacterial and antiribosomal activities and selectivities. The 6′-N-(2-hydroxyethyl) modification results in a moderate increase in prokaryotic/eukaryotic ribosomal selectivity, whereas the 1-N-(4-amino-2S-hydroxybutyryl) modification has the opposite effect. When combined in plazomicin, the effects of the two groups on ribosomal selectivity cancel each other out, leading to the prediction that plazomicin will exhibit ototoxicity comparable to those of the parent and the current clinical Aminoglycoside Antibiotics gentamicin and tobramycin, as borne out by ex vivo studies with mouse cochlear explants. The 6′-N-(2-hydroxyethyl) modification restores antibacterial activity in the presence of the AAC(6′) Aminoglycoside-modifying enzymes, while the 1-N-(4-amino-2S-hydroxybutyryl) modification overcomes resistance to the AAC(2′) class but is still affected to some extent by the AAC(3) class. Neither modification is able to circumvent the ArmA ribosomal methyltransferase-induced Aminoglycoside resistance. The use of phenyltriazenyl protection for the secondary amino group of sisomicin facilitates the synthesis of each derivative and their characterization through the provision of sharp NMR spectra for all intermediates
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synthesis antiribosomal and antibacterial activity of 4 o glycopyranosyl paromomycin Aminoglycoside Antibiotics
MedChemComm, 2014Co-Authors: Weiwei Chen, Andrea Vasella, Erik C Bottger, Takahiko Matsushita, Dimitri Shcherbakov, Heithem Boukari, David CrichAbstract:A series of 4′-O-glycopyranosyl paromomycin analogs and a 4′-O-(glucosyloxymethyl) analog were synthesized and evaluated for their ribosomal activity to determine the influence of the glycosyl moiety on drug activity and selectivity. Antibacterial activity against clinical strains of Escherichia coli and Staphylococcus aureus was also investigated. While all compounds were less active than paromomycin itself, differences in activity were seen between the gluco-, manno-, and galactopyranosyl series and between individual anomers. These differences in activity, which are discussed in terms of variations in affinity for the ribosomal decoding A site, may prove useful in the design of subsequent generations of improved Aminoglycoside Antibiotics with reduced toxicity.
Frank Schweizer - One of the best experts on this subject based on the ideXlab platform.
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antibacterial activities of Aminoglycoside Antibiotics derived cationic amphiphiles polyol modified neomycin b kanamycin a amikacin and neamine based amphiphiles with potent broad spectrum antibacterial activity
Journal of Medicinal Chemistry, 2010Co-Authors: Smritilekha Bera, George G Zhanel, Frank SchweizerAbstract:Cationic amphiphiles containing multiple positively charged amino functions define a structurally diverse class of antibacterials with broad-spectrum activity and different modes of action. Oligocationic amphiphiles have been used as Antibiotics to treat infections and as antiseptics and disinfectants for decades with little or no occurrence of resistance. We have prepared a novel class of cationic amphiphiles termed Aminoglycoside Antibiotics-derived amphiphiles in which the polyol scaffold of the Aminoglycosides neomycin B, kanamycin A, amikacin, and neamine has been uniformly decorated with hydrophobic residues in the form of polycarbamates and polyethers. Our results show that the nature of the polyol modification as well as the nature of the Aminoglycoside Antibiotics has a strong effect on the antibacterial potency. The most potent antibacterials are polyol-modified neomycin B-based amphiphiles containing unsubstituted aromatic rings. These analogues exhibit up to 256-fold enhanced antibacterial activity against resistant strains when compared to neomycin B while retaining most of their activity against neomycin B-susceptible strains.
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antibacterial activities of Aminoglycoside Antibiotics derived cationic amphiphiles polyol modified neomycin b kanamycin a amikacin and neamine based amphiphiles with potent broad spectrum antibacterial activity
Journal of Medicinal Chemistry, 2010Co-Authors: Smritilekha Bera, George G Zhanel, Frank SchweizerAbstract:Cationic amphiphiles containing multiple positively charged amino functions define a structurally diverse class of antibacterials with broad-spectrum activity and different modes of action. Oligocationic amphiphiles have been used as Antibiotics to treat infections and as antiseptics and disinfectants for decades with little or no occurrence of resistance. We have prepared a novel class of cationic amphiphiles termed Aminoglycoside Antibiotics-derived amphiphiles in which the polyol scaffold of the Aminoglycosides neomycin B, kanamycin A, amikacin, and neamine has been uniformly decorated with hydrophobic residues in the form of polycarbamates and polyethers. Our results show that the nature of the polyol modification as well as the nature of the Aminoglycoside Antibiotics has a strong effect on the antibacterial potency. The most potent antibacterials are polyol-modified neomycin B-based amphiphiles containing unsubstituted aromatic rings. These analogues exhibit up to 256-fold enhanced antibacterial act...
Tadashi Eguchi - One of the best experts on this subject based on the ideXlab platform.
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biosynthetic enzymes for the Aminoglycosides butirosin and neomycin
Methods in Enzymology, 2009Co-Authors: Fumitaka Kudo, Tadashi EguchiAbstract:Butirosin and neomycin belong to a family of clinically valuable 2-deoxystreptamine (2DOS)-containing Aminoglycoside Antibiotics. The biosynthetic gene clusters for butirosin and neomycin were identified in 2000 and in 2005, respectively. In recent years, most of the enzymes encoded in the gene clusters have been characterized, and thus almost all the biosynthetic steps leading to the final Antibiotics have been understood. This knowledge could shed light on the complex biosynthetic pathways for other related structurally diverse Aminoglycoside Antibiotics. In this chapter, the enzymatic reactions in the biosynthesis of butirosin and neomycin are reviewed step by step.
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structure of 2 deoxy scyllo inosose synthase a key enzyme in the biosynthesis of 2 deoxystreptamine containing Aminoglycoside Antibiotics in complex with a mechanism based inhibitor and nad
Proteins, 2007Co-Authors: Eriko Nango, Takashi Kumasaka, Toshifumi Hirayama, Nobuo Tanaka, Tadashi EguchiAbstract:: A key enzyme in the biosynthesis of clinically important Aminoglycoside Antibiotics is 2-deoxy-scyllo-inosose synthase (DOIS), which catalyzes carbocycle formation from D-glucose-6-phosphate to 2-deoxy-scyllo-inosose through a multistep reaction. This reaction mechanism is similar to the catalysis by dehydroquinate synthase (DHQS) of the cyclization of 3-deoxy-D-arabino-heputulosonate-7-phosphate to dehydroquinate in the shikimate pathway, but significant dissimilarity between these enzymes is also known, particularly in the stereochemistry of the phosphate elimination reaction and the cyclization. Here, the crystal structures of DOIS from Bacillus circulans and its complex with the substrate analog inhibitor carbaglucose-6-phosphate, NAD+, and Co2+ have been determined to provide structural insights into the reaction mechanism. The complex structure shows that an active site exists between the N-terminal and C-terminal domains and that the inhibitor coordinates a cobalt ion in this site. Two subunits exist as a dimer in the asymmetric unit. The two active sites of the dimer were observed to be different. One contains a dephosphorylated compound derived from the inhibitor and the other includes the inhibitor without change. The present study suggested that phosphate elimination proceeds through syn-elimination assisted by Glu 243 and the aldol condensation proceeds via a boat conformation. Also discussed are significant similarities and dissimilarities between DOIS and DHQS, particularly in terms of the structure at the active site and the reaction mechanism.
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Crystallization and X-ray analysis of 2-deoxy-scyllo-inosose synthase, the key enzyme in the biosynthesis of 2-deoxystreptamine-containing Aminoglycoside Antibiotics.
Acta Crystallographica Section F Structural Biology and Crystallization Communications, 2005Co-Authors: Eriko Nango, Takashi Kumasaka, Nobuo Tanaka, Katsumi Kakinuma, Takao Sato, Tadashi EguchiAbstract:The crystallization of 2-deoxy-scyllo-inosose synthase, the key enzyme in the biosynthesis of 2-deoxystreptamine-containing Aminoglycoside Antibiotics, is reported. A recombinant 2-deoxy-scyllo-inosose synthase from Bacillus circulans has been crystallized at 277 K using PEG 4000 as precipitant. The diffraction pattern of the crystal extends to 2.30 A resolution at 100 K using synchrotron radiation at the Photon Factory. The crystals are monoclinic and belong to space group P2{sub 1}, with unit-cell parameters a = 80.5, b = 70.4, c = 83.0 A, β = 117.8°. The presence of two molecules per asymmetric unit gives a crystal volume per protein weight (V{sub M}) of 2.89 A{sup 3} Da{sup −1} and a solvent constant of 57.4% by volume.
Smritilekha Bera - One of the best experts on this subject based on the ideXlab platform.
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antibacterial activities of Aminoglycoside Antibiotics derived cationic amphiphiles polyol modified neomycin b kanamycin a amikacin and neamine based amphiphiles with potent broad spectrum antibacterial activity
Journal of Medicinal Chemistry, 2010Co-Authors: Smritilekha Bera, George G Zhanel, Frank SchweizerAbstract:Cationic amphiphiles containing multiple positively charged amino functions define a structurally diverse class of antibacterials with broad-spectrum activity and different modes of action. Oligocationic amphiphiles have been used as Antibiotics to treat infections and as antiseptics and disinfectants for decades with little or no occurrence of resistance. We have prepared a novel class of cationic amphiphiles termed Aminoglycoside Antibiotics-derived amphiphiles in which the polyol scaffold of the Aminoglycosides neomycin B, kanamycin A, amikacin, and neamine has been uniformly decorated with hydrophobic residues in the form of polycarbamates and polyethers. Our results show that the nature of the polyol modification as well as the nature of the Aminoglycoside Antibiotics has a strong effect on the antibacterial potency. The most potent antibacterials are polyol-modified neomycin B-based amphiphiles containing unsubstituted aromatic rings. These analogues exhibit up to 256-fold enhanced antibacterial activity against resistant strains when compared to neomycin B while retaining most of their activity against neomycin B-susceptible strains.
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antibacterial activities of Aminoglycoside Antibiotics derived cationic amphiphiles polyol modified neomycin b kanamycin a amikacin and neamine based amphiphiles with potent broad spectrum antibacterial activity
Journal of Medicinal Chemistry, 2010Co-Authors: Smritilekha Bera, George G Zhanel, Frank SchweizerAbstract:Cationic amphiphiles containing multiple positively charged amino functions define a structurally diverse class of antibacterials with broad-spectrum activity and different modes of action. Oligocationic amphiphiles have been used as Antibiotics to treat infections and as antiseptics and disinfectants for decades with little or no occurrence of resistance. We have prepared a novel class of cationic amphiphiles termed Aminoglycoside Antibiotics-derived amphiphiles in which the polyol scaffold of the Aminoglycosides neomycin B, kanamycin A, amikacin, and neamine has been uniformly decorated with hydrophobic residues in the form of polycarbamates and polyethers. Our results show that the nature of the polyol modification as well as the nature of the Aminoglycoside Antibiotics has a strong effect on the antibacterial potency. The most potent antibacterials are polyol-modified neomycin B-based amphiphiles containing unsubstituted aromatic rings. These analogues exhibit up to 256-fold enhanced antibacterial act...
Xinshan Ye - One of the best experts on this subject based on the ideXlab platform.
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synthesis of neamine derived pseudodisaccharides by stereo and regio selective functional group transformations
Organic and Biomolecular Chemistry, 2009Co-Authors: Lijuan Pang, Lihe Zhang, Dan Wang, Xinshan YeAbstract:Neamine is normally found as a core structure of Aminoglycoside Antibiotics. In order to understand the relationship between the antibiotic activity and the configurations of the functional groups of neamine, a series of novel neamine analogues with functional group manipulations on the 2-deoxystreptamine (2-DOS) ring or the sugar ring were designed and synthesized. The synthetic approach involved the construction of 2-DOS derivatives by catalytic Ferrier II rearrangement, stereo- and regio-selective functional group transformations, glycosyl coupling reaction, and global deprotection. Of the synthetic neamine analogues, four compounds showed comparable 16S rRNA binding affinities with neamine, whereas they displayed lower binding affinities towards 18S rRNA than neamine, implying a lower toxicity to mammals. This strategy might have applications in the chemical synthesis of other neamine derivatives and new Aminoglycoside Antibiotics with improved biological activities.