Benzylidene lactam compound, KNK437, a novel inhibitor of acquisition of thermotolerance and heat shock protein induction in human colon carcinoma cells.
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Cells exposed to heat or other types of stressors transiently synthesize a group of proteins known as heat shock proteins (HSPs). A nonlethal heat treatment can elicit in the cells an ability to resist subsequent lethal heat treatments. We report here that a novel benzylidene lactam compound, KNK437, dose-dependently inhibited the acquisition of thermotolerance and the induction of various HSPs including HSP105, HSP70, and HSP40 in COLO 320DM (human colon carcinoma) cells. The induction of heat-inducible HSP70, which is reported to be involved in the development of thermotolerance, was inhibited at mRNA levels by treatment with KNK437. This compound also inhibited the acquisition of thermotolerance as developed by sodium arsenite. However, it did not increase thermosensitivity in nontolerant cells. The effect of KNK437 was much greater than that of quercetin, a bioflavonoid that was previously reported to inhibit the acquisition of thermotolerance as well as the induction of HSPs. We conclude that this drug is a novel inhibitor of the acquisition of thermotolerance caused by the induction of HSPs. (+info)
In vitro activity of DU-6681a, an active form of the new oral carbapenem compound DZ-2640, in comparison with that of R-95867, faropenem and oral cephalosporins.
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We compared the in vitro antibacterial activity of DU-6681a against Gram-positive and Gram-negative bacteria with that of R-95867, faropenem and oral cephalosporins such as cefcapene, cefotiam and cefpodoxime. DU-6681a is an active form of the new oral carbapenem compound DZ-2640, which is an ester-type prodrug, and R-95867 is an active form of the oral carbapenem CS-834. Against most Gram-positive bacteria, DU-6681a was as active as or two- to 16-fold more potent than R-95867 and faropenem in terms of MIC(90), and comparable to or two- to 64-fold more effective than the cephalosporins. Against most Gram-negative bacteria, the activity of DU-6681a was the same as or two- to 16-fold more potent than that of R-95867, and comparable to or two- to 2048-fold higher than that of faropenem and the cephalosporins. (+info)
High resolution X-ray crystallography shows that ascorbate is a cofactor for myrosinase and substitutes for the function of the catalytic base.
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Myrosinase, an S-glycosidase, hydrolyzes plant anionic 1-thio-beta-d-glucosides (glucosinolates) considered part of the plant defense system. Although O-glycosidases are ubiquitous, myrosinase is the only known S-glycosidase. Its active site is very similar to that of retaining O-glycosidases, but one of the catalytic residues in O-glycosidases, a carboxylate residue functioning as the general base, is replaced by a glutamine residue. Myrosinase is strongly activated by ascorbic acid. Several binary and ternary complexes of myrosinase with different transition state analogues and ascorbic acid have been analyzed at high resolution by x-ray crystallography along with a 2-deoxy-2-fluoro-glucosyl enzyme intermediate. One of the inhibitors, d-gluconhydroximo-1,5-lactam, binds simultaneously with a sulfate ion to form a mimic of the enzyme-substrate complex. Ascorbate binds to a site distinct from the glucose binding site but overlapping with the aglycon binding site, suggesting that activation occurs at the second step of catalysis, i.e. hydrolysis of the glycosyl enzyme. A water molecule is placed perfectly for activation by ascorbate and for nucleophilic attack on the covalently trapped 2-fluoro-glucosyl-moiety. Activation of the hydrolysis of the glucosyl enzyme intermediate is further evidenced by the observation that ascorbate enhances the rate of reactivation of the 2-fluoro-glycosyl enzyme, leading to the conclusion that ascorbic acid substitutes for the catalytic base in myrosinase. (+info)
Microbiological and pharmacodynamic considerations in the treatment of infection due to antimicrobial-resistant Streptococcus pneumoniae.
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The incidence of antimicrobial-resistant strains of Streptococcus pneumoniae has increased alarmingly in recent years. The problem is exacerbated by the global spread of resistant organisms. Currently, the incidence of penicillin-resistant pneumococci isolated from clinical specimens in the United States is > or = 35%. For empirical oral treatment of community-acquired respiratory infections, 3 choices are available: beta-lactam agents, macrolides, and fluoroquinolones. In considering the therapeutic efficacy of these agents, it is essential to also take pharmacokinetic and pharmacodynamic (PK/PD) factors into account. Many drugs are effective against penicillin-susceptible strains. However, the higher the minimum inhibitory concentration of penicillin, the more likely that cross-resistance to beta-lactam agents and macrolides will occur. Currently, the incidence of fluoroquinolone-resistant pneumococci is low; it is proposed that adequate dosing based on the PK/PD properties of fluoroquinolones may help reduce the emergence of resistant organisms. Prudent use of all antimicrobials is essential to decrease the emergence of strains resistant to these agents. (+info)
The evolving threat of antibiotic resistance in Europe: new data from the Alexander Project.
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The Alexander Project was established in 1992 to examine the antimicrobial susceptibility of community-acquired lower respiratory tract bacterial pathogens to a range of compounds. Since then it has expanded both geographically and in the number of antimicrobial agents tested. Within Europe, the most recent data have confirmed that the prevalence of penicillin resistance among isolates of Streptococcus pneumoniae is high in France and Spain, with both intermediate (MIC 0.12-1 mg/L) and resistant (MIC > or = 2 mg/L) phenotypes, and combined resistance rates of >50%. Macrolide resistance is increasing generally both among penicillin-resistant and penicillin-susceptible isolates of S. pneumoniae and its prevalence now exceeds that of penicillin resistance, overall (16.5% and 10.4%, respectively, in 1996; 21.9% and 14.1% in 1997; 16.5% and 11.6% in 1998). Beta-lactamase production was the principal mechanism of resistance observed among isolates of Haemophilus influenzae and Moraxella catarrhalis. (+info)
'pH-jump' crystallographic analyses of gamma-lactam-porcine pancreatic elastase complexes.
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beta-Lactams inhibit a range of enzymes via acylation of nucleophilic serine residues. Certain gamma-lactam analogues of monocyclic beta-lactams have also been shown to be reversible inhibitors of porcine pancreatic elastase (PPE), forming acyl-enzyme complexes that are stable with respect to hydrolysis. Crystallographic analysis at pH 5 of an acyl-enzyme complex formed with PPE and one of these inhibitors revealed the ester carbonyl located in the oxyanion hole in a similar conformation to that observed in the structure of a complex formed between a heptapeptide (beta-casomorphin-7) and PPE. Only weak electron density was observed for the His-57 side chain in its 'native' conformation. Instead, the His-57 side chain predominantly adopted a conformation rotated approx. 90 degrees from its normal position. PPE-gamma-lactam crystals were subjected to 'pH-jumps' by placing the crystals in a buffer of increased pH prior to freezing for data collection. The results indicate that the conformation of the gamma-lactam-derived acyl-enzyme species in the PPE active site is dependent on pH, a result having implications for the analysis of other serine protease-inhibitor structures at non-catalytic pH values. The results help to define the stereoelectronic relationship between the ester of the acyl-enzyme complex, the side chain of His-57 and the incoming nucleophile during the reversible (de)acylation steps, implying it is closely analogous to the hydrolytic deacylation step during catalytic peptide hydrolysis. (+info)
RNA polymerase inhibitors with activity against rifampin-resistant mutants of Staphylococcus aureus.
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A collection of rifampin-resistant mutants of Staphylococcus aureus with characterized RNA polymerase beta-subunit (rpoB) gene mutations was cross-screened against a number of other RNA polymerase inhibitors to correlate susceptibility with specific rpoB genotypes. The rpoB mutants were cross-resistant to streptolydigin and sorangicin A. In contrast, thiolutin, holomycin, corallopyronin A, and ripostatin A retained activity against the rpoB mutants. The second group of inhibitors may be of interest as drug development candidates. (+info)
Regulation of cell proliferation, gene expression, production of cytokines, and cell cycle progression in primary human T lymphocytes by piperlactam S isolated from Piper kadsura.
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Effects of piperlactam S (C(17)H(13)NO(4); mol. wt. 295) isolated from Piper kadsura on phytohemagglutinin (PHA) stimulated cell proliferation were studied in primary culture of human T cells. The results showed that piperlactam S suppressed T cell proliferation at about 0 to 12 h after stimulation with PHA. Synthesis of total cellular proteins and RNA in activated cell cultures was also suppressed. The inhibitory action of piperlactam S was not through direct cytotoxicity. Cell cycle analysis indicated that piperlactam S arrested the cell cycle progression of activated T cells from the G(1) transition to the S phase. In an attempt to further localize the point in the cell cycle at which arrest occurred, a set of key regulatory events leading to the G(1)/S boundary, including gene expression of cytokines and c-Fos protein synthesis, was examined. Piperlactam S suppressed, in activated T lymphocytes, the production and mRNA expression of cytokines such as interleukin-2 (IL-2), IL-4, and interferon-gamma in a dose-dependent manner. In addition, Western blot analysis indicated that c-Fos protein expressed in activated T lymphocytes was decreased by piperlactam S. Results of kinetic study indicated that inhibitory effects of piperlactam S on IL-2 mRNA expressed in T cells might be related to blocking c-Fos protein synthesis. Thus, the suppressant effects of piperlactam S on proliferation of T cells activated by PHA seemed to be mediated, at least in part, through inhibition of early transcripts of T cells, especially those of important cytokines, IL-2, IL-4, and arresting cell cycle progression in the cells. (+info)