共查询到20条相似文献,搜索用时 31 毫秒
1.
Tomoaki Miura Satomi Natsume Kenichi Kanemoto Eiki Shitara Hideki Fushimi Takuji Yoshida Keiichi Ajito 《Bioorganic & medicinal chemistry》2010,18(7):2735-2747
The design and synthesis of 16-membered azalides modified at the C-15 and 4″ positions are described. The compounds we report here are characterized by an arylpropenyl group attached to the C-15 position of macrolactone and a carbamoyl group at the C-4″ position in a neutral sugar. Introduction of alkylcarbamoyl groups to the C-4″ position was regioselectively achieved by unique and convenient methods via acyl migration. As a result of optimization at the C-3 and 15 positions, several compounds were found to have potent activity against mef- and erm-resistant bacterial strains. These results suggest that 16-membered azalides could be promising compounds as clinical candidates. 相似文献
2.
Conversion of heterocyclic and aromatic aldehydes to the corresponding carboxylic acids was carried out using Acetobacter rancens IFO3297, A. pasteurianus IFO13753 and Serratia liquefaciens LF14. IFO3297 produced 110 g 2-furoic acid l(-1) from furfural with a 95% molar yield. 5-Hydroxymethyl-2-furancarboxylic acid was produced from the corresponding aldehyde by using whole cells LF14. IFO13753 and LF14 both converted isophthalaldehyde, 2,5-furandicarbaldehyde, 2,5-thiophenedicarbaldehyde and 2,2' biphenyldicarbaldehyde to the corresponding formylcarboxylic acid with 86-91% molar yields. 相似文献
3.
Escherichia coli CU1, a clinical isolate recovered in Japan in 1997, was found to be highly-resistant to both 14-membered and 16-membered ring macrolide antibiotics. A crude extract prepared from strain CU1 inactivated 14-, 15- and 16-membered ring macrolides in the presence of ATP and the Rf value of inactivated oleandomycin was identical to that of oleandomycin 2'-phosphate. This suggested that strain CU1 produced the enzyme macrolide 2'-phosphotransferase [MPH(2')]. Substrate specificity of the crude enzyme from strain CU1 against 14-, 15- and 16-membered ring macrolides was basically similar to that of MPH(2')II from strain BM2506, differing in that the former more effectively inactivated roxithromycin and tylosin. Subsequent attempts were made to clone the novel mph gene encoding for MPH(2') in strain CU1. The mph gene carried by strain CU1 was located on nontransmissible plasmid DNA, designated pCU001. Its molecular weight, estimated by agarose electrophoresis, was approximately 57 kD. The DNA sequence of the cloned mph gene from the Japanese isolate CU1 was identical to that of mphB, which until now had only been recovered in France. The variance in the substrate specificity of MPH(2')II from each strain led us to speculate that other factors in the reaction affect the enzymatic inactivation activity. 相似文献
4.
We have reported that the gene mph(C) (formally referred to as 'mphBM') is located on plasmid pMS97 342 bp downstream of the msr(A) gene. msr(A) specifies resistance to macrolides by ABC-transporter-mediated efflux, and mph(C) has 49% identity to the amino acid sequence of MPH(2')II, which encodes a phosphotransferase that inactivates some macrolide antibiotics. A strain of Staphylococcus aureus NCTC8325 containing plasmid pMS97 inactivated unlabeled and (14)C-labeled erythromycin when tested by bioautographic and radioautographic techniques. In addition to erythromycin, other 14-membered ring macrolides (except for ketolides), 15-membered ring macrolides and 16-membered ring macrolides, mycinamicin, rosamicin and YM133, were inactivated by the strain. Erythromycin inactivation products produced by the strain carrying pMS97 were completely different from those produced by Escherichia coli BM694 bearing plasmid pAT63, which contains the ereA gene encoding an esterase that hydrolyzes macrolide lactones. Constructs formed with the msr(A) and mph(C) genes, and with the msr(A), mph(C) and erm(Y) genes, showed erythromycin-inactivating activity, but another construct built with the mph(C) gene alone failed to show such activity. This result suggests that any region of the msr(A) gene is needed for the expression of mph(C). 相似文献
5.
Koichi Mitsukura Yukihide Sato Toyokazu Yoshida Toru Nagasawa 《Biotechnology letters》2005,26(21):1643-1648
Conversion of heterocyclic and aromatic aldehydes to the corresponding carboxylic acids was carried out using Acetobacter rancens IFO3297, A. pasteurianus IFO13753 and Serratia liquefaciens LF14. IFO3297 produced 110g 2-furoic acid l-1 from furfural with a 95% molar yield. 5-Hydroxymethyl-2-furancarboxylic acid was produced from the corresponding aldehyde by using whole cells LF14. IFO13753 and LF14 both converted isophthalaldehyde, 2,5-furandicarbaldehyde, 2,5-thiophenedicarbaldehyde and 2,2 biphenyldicarbaldehyde to the corresponding formylcarboxylic acid with 86--91% molar yields.Revisions requested 21 July 2004; Revisions received 7 September 2004 相似文献
6.
The origin of the skeletal carbons in the lactone ring of 16-membered macrolide antiobiotics has been studied. 13C-labeled antibiotics leucomycin and tylosin, have been obtained from the culture broth of Streptomyces kitasatoensis 66-14-3 and Streptomyces fradiae C-373, respectively in the presence of appropriate 13C-labeled precursors, and 13C NMR spectra of the antibiotics thus obtained have been measured. It was shown that the aglycone of leucomycin A3 is derived from five acetates, one propionate, one butyrate, and an unknown precursor corresponding to two carbons. The formyl carbon which is characteristic of the basic 16-membered macrolides orginates from C-4 butyrate. On the other hand, the aglycone of tylosin is formed from two acetates, five propionates and one butyrate. Butyric acid and ethylmalonic acid are metabolized to propionyl-CoA or methylmolonyl-CoA through a pathway involving methylmalonyl-CoA mutase, and subsequently incorporated into the lactone ring of tylosin. 相似文献
7.
The specificity and mode of action of an acid proteinase (EC 3.4.23.6) from Aspergillus saitoi were investigated with oxidized B-chain of insulin, angiotensin II and bradykinin. Further purification of acid proteinase was performed with N,O-dibenzyloxycarbonyl-tyrosine hexamethylene-diamino-Sepharose 4B affinity chromatography and isoelectric focusing. The purified enzyme was free of any other proteolytic activity demonstrated in Asp. saitoi. Acid proteinase from Asp. saitoi hydrolyzed primarily two peptide bonds in the oxidized B-chain of insulin, the Leu(15)-Tyr(16) bond and the Phe(24)-Phe(25) bond. Additional cleavages of the bonds His(10)-Leu(11), Ala(14)-Leu(15) and Tyr(16)-Leu(17) were also noted. Primary splitting sites at Leu(15)-Tyr(16) and Phe(24-)-Phe(25) with acid proteinase from Asp. saitoi were identical with those reported in the work of cathepsin D (EC 3.4.23.5) from human erythrocyte. Hydrolysis of angiotensin II was observed at the Tyr(4)-Ile(5) bond. In conclusion, peptide bonds which have a hydrophobic amino acid such as phenylalanine, tyrosine, leucine and isoleucine in the P'1 position (as defined by Berger and Schechter, [29]) are preferentially cleaved by the trypsinogenactivating acid proteinase from Asp. saitoi. 相似文献
8.
An efficient method for the synthesis of diverse 9a-carbamoyl- and 9a-thiocarbamoyl-3-decladinosyl-6-hydroxy and 3-decladinosyl-6-methoxy derivatives of 15-membered azalides has been developed. These derivatives bear various alkyl and aryl groups attached to macrolide scaffold through urea or thiourea moieties at 9a position. Chemical transformations of hydroxy group at position C-3 afforded range of ketolides, anhydrolides, hemiketals, cyclic ethers, and acylides. It has been shown that 6-hydroxy and 6-methoxy derivatives undergo different chemical transformations under otherwise identical reaction conditions. Antimicrobial properties of prepared compounds were evaluated. 相似文献
9.
M Di Giambattista Y Engelborghs E Nyssen C Cocito 《The Journal of biological chemistry》1987,262(18):8591-8597
The synergistic effect of type A (virginiamycin M (VM)) and type B (virginiamycin S (VS)) synergimycins and their antagonistic effect against erythromycin (a 14-membered macrolide) for binding to the large ribosomal subunit (50 S) have been related. This investigation has now been extended to 16-membered macrolides (leucomycin A3 and spiramycin) and to lincosamides (lincomycin). A dissociation of VS-ribosome complexes was induced as well by 16-membered macrolides as by lincosamides. The observed dissociation rate constant of VS-ribosome complexes was identified with the kappa-vs in the case of 16-membered macrolides, but linearly related to lincomycin concentration, suggesting a direct binding of the latter antibiotic to VS-ribosome complexes and the triggering of a conformational change of particles entailing VS release. Two different mechanisms were also involved in the VM-promoted reassociation to ribosomes of VS previously displaced by either macrolides or lincosamides. By binding to lincosamide-ribosome complexes, VM induced a conformational change of ribosomes resulting in higher affinity for VS and lower affinity for lincosamides. On the contrary, an incompatibility for a simultaneous binding of VM and 16-membered macrolides to ribosomes was observed. These results have been interpreted by postulating specific (nonoverlapping) and aspecific (overlapping) antibiotic binding sites at the peptidyltransferase domain. All the kinetic constants of five antibiotic families (type A and B synergimycins, 14- and 16-membered macrolides, and lincosamides) and a topological model of peptidyltransferase are presently available. 相似文献
10.
Analogues of 16-membered peptide antibiotic zervamicin IIB with the Gln3 and Gln11 residues 15N-labeled at the C alpha-atoms were synthesized by coupling the antibiotic segments (1-4), (5-9), and (10-16). In turn, these were prepared by a stepwise chain elongation in solution starting from their C-termini using benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) as an activating agent. The sterically hindered 2-aminoisobutyric acid was introduced by the BOP-dimethylaminopyridine system with the preactivation of the carboxyl component. The segment condensation was performed with the use of the 6-trifluoromethylbenzotriazol-1-yloxy-tris(pyrrolidino)phosphonium hexafluorophosphate activating reagent. The homogeneity of the resulting zervamicin analogues was confirmed by HPLC, and their structures were proved by NMR spectroscopy and FAB mass spectrometry. 相似文献
11.
Molecular cloning and functional analysis of a novel macrolide-resistance determinant, mefA, from Streptococcus pyogenes 总被引:4,自引:0,他引:4
Joanna Clancy Joan Petitpas Fadia Dib-Hajj Wei Yuan Melissa Cronan Ajith V. Kamath Jay Bergeron & James A. Retsema 《Molecular microbiology》1996,22(5):867-879
Several streptococcal strains had an uncharacterized mechanism of macrolide resistance that differed from those that had been reported previously in the literature. This novel mechanism conveyed resistance to 14- and 15-membered macrolides, but not to 16-membered macrolides, lincosamides or analogues of streptogramin B. The gene encoding this phenotype was cloned by standard methods from total genomic digests of Streptococcus pyogenes 02C1064 as a 4.7 kb heterologous insert into the low-copy vector, pACYC177, and expressed in several Escherichia coli K-12 strains. The location of the macrolide- resistance determinant was established by functional analysis of deletion derivatives and sequencing. A search for homologues in the genetic databases confirmed that the gene is a novel one with homology to membrane-associated pump proteins. The macrolide-resistance coding sequence was subcloned into a pET23a vector and expressed from the inducible T7 promoter on the plasmid in E. coli BL21(DE3). Physiological studies of the cloned determinant, which has been named mefA for macrolide efflux, provide evidence for its mechanism of action in host bacteria. E. coli strains containing the cloned determinant maintain lower levels of intracellular erythromycin when this compound is added to the external medium than isogenic clones without mefA . Furthermore, intracellular accumulation of [14 C]-erythromycin in the original S. pyogenes strain was always lower than that observed in erythromycin-sensitive strains. This is consistent with a hypothesis that the gene encodes a novel antiporter function which pumps erythromycin out of the cell. The gene appears to be widely distributed in S. pyogenes strains, as demonstrated by primer-specific synthesis using the polymerase chain reaction. 相似文献
12.
Lampa A Ehrenberg AE Vema A Åkerblom E Lindeberg G Danielson UH Karlén A Sandström A 《Bioorganic & medicinal chemistry》2011,19(16):4917-4927
Macrocyclization is a commonly used strategy to preorganize HCV NS3 protease inhibitors in their bioactive conformation. Moreover, macrocyclization generally leads to greater stability and improved pharmacokinetic properties. In HCV NS3 protease inhibitors, it has been shown to be beneficial to include a vinylated phenylglycine in the P2 position in combination with alkenylic P1' substituents. A series of 14-, 15- and 16-membered macrocyclic HCV NS3 protease inhibitors with the linker connecting the P2 phenylglycine and the alkenylic P1' were synthesized by ring-closing metathesis, using both microwave and conventional heating. Besides formation of the expected macrocycles in cis and trans configuration as major products, both ring-contracted and double-bond migrated isomers were obtained, in particular during formation of the smaller rings (14- and 15-membered rings). All inhibitors had K(i)-values in the nanomolar range, but only one inhibitor type was improved by rigidification. The loss in inhibitory effect can be attributed to a disruption of the beneficial π-π interaction between the P2 fragment and H57, which proved to be especially deleterious for the d-phenylglycine epimers. 相似文献
13.
The syntheses and olfactory evaluations of eight new macrocyclic musks with a 1,6-dioxa structure (1a-d and 1'a-d) as well as of twelve optically active 3-methyl macrolides (5a-c and 5'a-c) are reported. These macrocycles were synthesized via intramolecular metathesis mediated by the Grubbs catalyst. Despite the absence of a C=O function, the 1,6-dioxa compounds, both unsaturated (1) and saturated (1'), possess musky odors similar to those of macrocyclic ketones and lactones. Especially 16-membered rings were found to display an intense and pleasant musk character. However, in the case of optically active 3-methyl macrolides (5, 5'), only the (R)-configured 15- and 16-membered rings had intense and pleasant musk notes. 相似文献
14.
MacB is an ABC-type membrane protein that exports only macrolide compounds containing 14- and 15-membered lactones, cooperating with a membrane fusion protein, MacA, and a multifunctional outer membrane channel, TolC. We determined the membrane topology of MacB by means of site-specific competitive chemical modification of single cysteine mutants. As a result, it was revealed that MacB is composed of four transmembrane (TM) segments with a cytoplasmic N-terminal nucleotide binding domain of about 270 amino acid residues and a periplasmic large hydrophilic polypeptide between TM segments 1 and 2 of about 200 amino acid residues. 相似文献
15.
A U Siddiqui W K Wilson K E Ruecker F D Pinkerton G J Schroepfer 《Chemistry and physics of lipids》1992,63(1-2):77-90
26-Oxygenated derivatives of delta 8(14)-15-ketosterols have been synthesized from (25R)-3 beta,26-diacetoxy-5 alpha-cholest-8(14)-en-15-one (IX) as part of a program to prepare potential metabolites and analogs of 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one (I), a potent regulator of cholesterol metabolism. Partial hydrolysis of IX gave a mixture, from which the 3 beta,26-diol II and the 26-acetate (XI) and 3 beta-acetate (X) monoesters were isolated. Mitsunobu reaction of XI followed by hydrolysis gave (25R)-3 alpha,26-dihydroxy-5 alpha-cholest-8(14)-en-15-one (VI). Oxidation of XI with pyridinium chlorochromate followed by hydrolysis of the acetate gave (25R)-26-hydroxy-5 alpha-cholest-8(14)-ene-3,15-dione (VII). Oxidation of X with Jones reagent followed by hydrolysis of the acetate gave (25R)-3 beta-hydroxy-15-keto-5 alpha-cholest-8(14)-en-26-oic acid (IVa). Jones oxidation of II gave (25R)-3,15-diketo-5 alpha-cholest-8(14)-en-26-oic acid (VII). 1H and 13C nuclear magnetic resonance assignments and analyses of mass spectral fragmentation data are presented for each of the new compounds and their derivatives. The 3,15-diketone VII was found to be highly active in lowering the levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in CHO-K1 cells, with a potency comparable to that of I. In contrast, 3 alpha,26-diol VI was less potent than I or VII. The two carboxylic acid analogs IVa and VIII were considerably less potent than VI in lowering the levels of HMG-CoA reductase activity. 相似文献
16.
Novel potent macrocyclic inhibitors of the hepatitis C virus NS3 protease: use of cyclopentane and cyclopentene P2-motifs 总被引:1,自引:0,他引:1
Bäck M Johansson PO Wångsell F Thorstensson F Kvarnström I Ayesa S Wähling H Pelcman M Jansson K Lindström S Wallberg H Classon B Rydergård C Vrang L Hamelink E Hallberg A Rosenquist S Samuelsson B 《Bioorganic & medicinal chemistry》2007,15(22):7184-7202
Several highly potent novel HCV NS3 protease inhibitors have been developed from two inhibitor series containing either a P2 trisubstituted macrocyclic cyclopentane- or a P2 cyclopentene dicarboxylic acid moiety as surrogates for the widely used N-acyl-(4R)-hydroxyproline in the P2 position. These inhibitors were optimized for anti HCV activities through examination of different ring sizes in the macrocyclic systems and further by exploring the effect of P4 substituent removal on potency. The target molecules were synthesized from readily available starting materials, furnishing the inhibitor compounds in good overall yields. It was found that the 14-membered ring system was the most potent in these two series and that the corresponding 13-, 15-, and 16-membered macrocyclic rings delivered less potent inhibitors. Moreover, the corresponding P1 acylsulfonamides had superior potencies over the corresponding P1 carboxylic acids. It is noteworthy that it has been possible to develop highly potent HCV protease inhibitors that altogether lack the P4 substituent. Thus the most potent inhibitor described in this work, inhibitor 20, displays a K(i) value of 0.41 nM and an EC(50) value of 9 nM in the subgenomic HCV replicon cell model on genotype 1b. To the best of our knowledge this is the first example described in the literature of a HCV protease inhibitor displaying high potency in the replicon assay and lacking the P4 substituent, a finding which should facilitate the development of orally active small molecule inhibitors against the HCV protease. 相似文献
17.
Characterization of PG2, an early endoPG produced by Sclerotinia sclerotiorum,expressed in yeast 总被引:2,自引:0,他引:2
An erythromycin esterase (molecular mass 51200 Da) was purified from Pseudomonas sp. GD100, which was isolated from a salmon hatchery sediment sample from Washington State. The pI of the protein was 4.5-4.8. The enzyme was inhibited by 1 mM mercuric acid, and had the substrate specificity for structurally related 14-membered macrolides, which decreased in the order of oleandomycin, erythromycin A and erythromycin A enol ether. The activity for erythromycin A varied with temperature, but the effect of pH was minimal at pH 6.0-9.0. The half-life of the enzyme was estimated to be 8.9 h at 35 degrees C and 0.23 h at 55 degrees C, and the activation energy of the catalytic reaction of erythromycin A was estimated at 16.2 kJ mol(-1). 相似文献
18.
Elinor Breiner-Goldstein Zohar Eyal Donna Matzov Yehuda Halfon Giuseppe Cimicata Moti Baum Assaf Rokney Analia
V Ezernitchi Andrew
N Lowell Jennifer
J Schmidt Haim Rozenberg Ella Zimmerman Anat Bashan Lea Valinsky Yojiro Anzai David
H Sherman Ada Yonath 《Nucleic acids research》2021,49(16):9560
Macrolides have been effective clinical antibiotics for over 70 years. They inhibit protein biosynthesis in bacterial pathogens by narrowing the nascent protein exit tunnel in the ribosome. The macrolide class of natural products consist of a macrolactone ring linked to one or more sugar molecules. Most of the macrolides used currently are semi-synthetic erythromycin derivatives, composed of a 14- or 15-membered macrolactone ring. Rapidly emerging resistance in bacterial pathogens is among the most urgent global health challenges, which render many antibiotics ineffective, including next-generation macrolides. To address this threat and advance a longer-term plan for developing new antibiotics, we demonstrate how 16-membered macrolides overcome erythromycin resistance in clinically isolated Staphylococcus aureus strains. By determining the structures of complexes of the large ribosomal subunit of Deinococcus radiodurans (D50S) with these 16-membered selected macrolides, and performing anti-microbial studies, we identified resistance mechanisms they may overcome. This new information provides important insights toward the rational design of therapeutics that are effective against drug resistant human pathogens. 相似文献
19.
T15 D region germ line amino acid sequences distinguished by monoclonal anti-idiotope antibody 总被引:2,自引:0,他引:2
S Nishinarita J L Claflin R Lieberman 《Journal of immunology (Baltimore, Md. : 1950)》1985,134(1):436-442
Monoclonal antibody NL16, prepared with phosphorylcholine (PC)-binding myeloma protein C.BBPC3 (C3), identified an idiotope (C3-16 Id) that was present on T15 IdX+ myeloma proteins (MP) C3, T15, and H8, but not the T15 IdX- MP M167 and M603. The binding of C3 to NL16 is PC inhibitable, indicating that C3-16 Id is site associated. Inhibition studies with PC-specific hybridoma proteins (HP) demonstrated that the T15-type L chain VK22 and elements of the H chain were required for C3-16 Id expression. Studies of amino acid sequences of these PC-binding HP and MP showed that VK22+, T15 IdX+ HP, and MP that use the T15 D region (YYGSS) sequences were always C3-16 Id+. However, the reverse was not true, because all but one VK22+, T15 IdX+ HP with D region sequence changes were C3-16 Id-. This suggested that NL16 defined a specificity mainly determined by the D region of the H chain. A direct test of this hypothesis with heterologous heavy/light chain recombinant molecules obtained from C3-16 Id+ and C3-16 Id- HP of known sequence, showed that the D region was critical to idiotope expression. Additionally, an examination of the amino acid sequences of VK22+, T15 IdX- HP, HPCG14, and HPCM6 suggest that profound changes in the D region may also alter the expression of T15 IdX (an Id defined by a multispecific antiserum from A/He mice). The C3-16 Id+ was found in anti-PC serum of most Ig haplotype-inbred strains except for CBA/J, C3H, and PL, which are all of the Igh-Cj haplotype. Amino acid sequences of PC-binding CBA and PL HP showed marked changes in the D region from the T15 type, and this may account for the C3-16 Id- character of Igh-Cj strains. 相似文献
20.
E Christensen T A Hagve M Gr?nn B O Christophersen 《Biochimica et biophysica acta》1989,1004(2):187-195
The beta-oxidation and esterification of medium-chain fatty acids were studied in hepatocytes from fasted, fed and fructose-refed rats. The beta-oxidation of lauric acid (12:0) was less inhibited by fructose refeeding and by (+)-decanoyl-carnitine than the oxidation of oleic acid was, suggesting a peroxisomal beta-oxidation of lauric acid. Little lauric acid was esterified in triacylglycerol fraction, except at high substrate concentrations or in the fructose-refed state. With [1-14C]myristic acid (14:0), [1-14C]lauric acid (12:0), [1-14C]octanoic acid (8:0) and [2-14C]adrenic acid (22:4(n - 6] as substrate for hepatocytes from carbohydrate-refed rats, a large fraction of the 14C-labelled esterified fatty acids consisted of newly synthesized palmitic acid (16:0), stearic acid (18:0) and oleic acid (18:1) while intact [1-14C]oleic acid substrate was esterified directly. With [9,10-3H]myristic acid as the substrate, small amounts of shortened 3H-labelled beta-oxidation intermediates were found. With [U-14C]palmitic acid, no shortened fatty acids were detected. It was concluded that when the mitochondrial fatty acid oxidation is down-regulated such as in the carbohydrate-refed state, medium-chain fatty acids can partly be retailored to long-chain fatty acids by peroxisomal beta-oxidation followed by synthesis of C16 and C16 fatty acids which can then stored as triacylglycerol. 相似文献