(33/173) Comparative distribution of azithromycin in lung tissue of patients given oral daily doses of 500 and 1000 mg.
OBJECTIVES: The administration of antibacterial agents should be optimized on the basis of their distribution to enhance drug exposure and obtain bacterial eradication. This study examines the pharmacokinetics of azithromycin in plasma, lung tissue and bronchial washing in patients after oral administration of 500 mg versus 1000 mg once daily for 3 days. PATIENTS AND METHODS: Samples of plasma, lung tissue and bronchial washing were obtained from a cohort of 48 patients during open-chest surgery for lung resection up to 204 h after the last drug dose, and assayed for antibiotic concentrations. RESULTS: Azithromycin was widely distributed within the lower respiratory tract and sustained levels of the drug were detectable at the last sampling time in lung tissue. Doubling the dose of the antibiotic resulted in a proportional increase in lung area under the curve (AUC, 1245.4 versus 2514.2 h x mg/kg) and peak tissue concentration (Cmax, 8.93 +/- 2.05 versus 18.6 +/- 2.20 mg/kg). The pharmacodynamic parameter AUC/MIC for susceptible and intermediate strains of Streptococcus pneumoniae (MICs 0.5 and 2 mg/L, respectively) increased after administration of the 1000 mg schedule compared with 500 mg (AUC/MIC0.5 2414 versus 1144 and AUC/MIC2 2112 versus 814.1 h x mg/kg, respectively) in pulmonary tissue. CONCLUSIONS: Lung exposure to azithromycin is increased proportionally by doubling the dose, which results in a predictable pharmacokinetic behaviour of the drug in the lower respiratory tract. (+info)
(34/173) Synthesis and biological evaluation of novel leucomycin analogues modified at the C-3 position. I. Epimerization and methylation of the 3-hydroxyl group.
The synthesis and biological evaluation of sixteen-membered macrolides modified at the C-3 position are described. 3-Epi-leucomycin A7 (9), 3-O-acyl-3-epi-leucomycin A7 analogues (11a-11e), 3-O-acylleucomycin A7 analogues (13b-13e) and 3-O-methylleucomycin analogues (16a, 16b and 22) were synthesized via fully protected intermediates (7, 5a, 5b and 20). After appropriate modification, subsequent deprotections were performed to furnish a variety of leucomycin analogues. Methylation of the 3-hydroxyl group was found to improve the pharmacoprofile of leucomycin antibiotics. 3-O-Methylrokitamycin (16b) showed enhanced antibacterial activity in vitro and 3,3''-di-O-methyl-4''-O-(3-methylbutyl)leucomycin V (22) exhibited improved metabolic stability in rat plasma in vitro. (+info)
(35/173) Reclassification of ATCC 9341 from Micrococcus luteus to Kocuria rhizophila.
Strain ATCC 9341, currently known as Micrococcus luteus, has been designated as a quality-control strain in a number of applications. It is also cited as the standard culture in several official methods and manuals, as well as the Code of Federal Regulations. Over the years, it has become apparent that ATCC 9341 does not resemble other M. luteus strains; however, its phenotypic characteristics alone were ambiguous. Recently, a polyphasic study was performed in which molecular data were combined with cytochemical properties and physiological characteristics. The results clearly indicate that ATCC 9341 is a member of the genus Kocuria. Thus, it is proposed to reclassify ATCC 9341 as Kocuria rhizophila and to alert users worldwide of this name change. (+info)
(36/173) Chain length distribution of the products formed in solanesyl diphosphate synthase reaction.
Factors that affect the termination of isoprenoid chain elongation catalyzed by prenyltransferase were investigated. The chain-length distribution of reaction products of solanesyl diphosphate synthase [EC 22.214.171.124] homogeneously purified from Micrococcus luteus changed dramatically according to the concentration of the complex formed between isopentenyl diphosphate and Mg2+ (IPP-Mg) in the reaction mixture. However, the concentration of the complex between farnesyl diphosphate and Mg2+ (FPP-Mg), the priming substrate for this synthase, did not affect the product distribution, provided that the concentration of IPP-Mg was maintained at a certain level. Thus, the level of IPP-Mg is decisive in affecting the chain length distribution of the products of the prenyltransferase reaction, and the Mg(2+)-dependent variability of product specificity so far observed can now be understood in terms of the effect of IPP-Mg concentration. (+info)
(37/173) Structural and topological studies on the lipid-mediated assembly of a membrane-associated lipomannan in Micrococcus luteus.
The biosynthesis of three mannolipids and the presence of a membrane-associated lipomannan in Micrococcus luteus (formerly Micrococcus lysodeikticus) were documented over 30 years ago. Structural and topological studies have been conducted to learn more about the possible role of the mannolipids in the assembly of the lipomannan. The major mannolipid has been purified and characterized as alpha-D-mannosyl-(1 --> 3)-alpha-D-mannosyl-(1 --> 3)-diacylglycerol (Man2-DAG) by negative-ion electrospray-ionization multistage mass spectrometry (ESI-MSn). Analysis of the fragmentation patterns indicates that the sn-1 position is predominantly acylated with a 12-methyltetradecanoyl group and the sn-2 position is acylated with a myristoyl group. The lipomannan is shown to be located on the exterior face of the cytoplasmic membrane, and not exposed on the surface of intact cells, by staining of intact protoplasts with fluorescein isothiocyanate (FITC)-linked concanavalin A (Con A). When cell homogenates of M. luteus are incubated with GDP-[3H]mannose (GDP-Man), [3H]mannosyl units are incorporated into Man1-2-DAG, mannosylphosphorylundecaprenol (Man-P-Undec) and the membrane-associated lipomannan. The addition of amphomycin, an inhibitor of Man-P-Undec synthesis, had no effect on the synthesis of Man1-2-DAG, but blocked the incorporation of [3H]mannose into Man-P-Undec and consequently the lipomannan. These results strongly indicate that GDP-Man is the direct mannosyl donor for the synthesis of Man1-2-DAG, and that the majority of the 50 mannosyl units in the lipomannan are derived from Man-P-Undec. Protease-sensitivity studies with intact and lysed protoplasts indicate that the active sites of the mannosyltransferases catalyzing the formation of Man1-2-DAG and Man-P-Undec are exposed on the inner face, and the Man-P-Undec-mediated reactions occur on the outer surface of the cytoplasmic membrane. Based on all of these results, a topological model is proposed for the lipid-mediated assembly of the membrane-bound lipomannan. (+info)
(38/173) Antibacterial activity and mechanism of action of tick defensin against Gram-positive bacteria.
Defensins are a major group of antimicrobial peptides and are found widely in vertebrates, invertebrates and plants. Invertebrate defensins have been identified from insects, scorpions, mussels and ticks. In this study, chemically synthesized tick defensin was used to further investigate the activity spectrum and mode of action of natural tick defensin. Synthetic tick defensin showed antibacterial activity against many Gram-positive bacteria but not Gram-negative bacteria and low hemolytic activity, characteristic of invertebrate defensins. Furthermore, bactericidal activity against pathogenic Gram-positive bacteria including Bacillus cereus, Enterococcus faecalis and methicillin-resistant Staphylococcus aureus was observed. However, more than 30 min was necessary for tick defensin to completely kill bacteria. The interaction of tick defensin with the bacterial cytoplasmic membrane and its ability to disrupt the membrane potential was analyzed. Tick defensin was able to disrupt the membrane potential over a period of 30-60 min consistent with its relatively slow killing. Transmission electron microscopy of Micrococcus luteus treated with tick defensin showed lysis of the cytoplasmic membrane and leakage of cellular cytoplasmic contents. These findings suggest that the primary mechanism of action of tick defensin is bacterial cytoplasmic membrane lysis. In addition, incomplete cell division with multiple cross-wall formation was occasionally seen in tick defensin-treated bacteria showing pleiotropic secondary effects of tick defensin. (+info)
(39/173) Proteomic analysis of the systemic immune response of Drosophila.
Improvements in two-dimensional gel electrophoresis, mass spectrometry, and bioinformatics provide new tools to characterize proteins involved in a physiological process, such as the immune response of the insect model Drosophila melanogaster. Profiling of the proteins present in the hemolymph (insect blood) of noninfected flies versus flies infected with bacteria or fungi was performed by two-dimensional gel electrophoresis, silver or Coomassie staining, and image analysis. Through this differential analysis, more than 70 out of 160 spots were up- or down-regulated by at least 5-fold after microbial infection. Coomassie staining, in-gel digestion, and database searches yielded the identity of a series of proteins that are directly involved in the Drosophila immune system. This included proteases, protease inhibitors, and recognition molecules such as prophenoloxydase-activating enzymes, serpins, and Gram-negative binding protein-like. Proteins with a potential function in the immune response were also identified, such as an odorant binding protein, peptidylglycine alpha-hydroxylating monooxygenase, and transferrin, affording new candidates for further investigation of innate immune mechanisms. Moreover, several molecules resulting from the cleavage of proteins were detected after the fungal infection. Altogether, this first differential proteomic analysis of the immune response of Drosophila paves the way for the study of proteins affected during innate immunity. (+info)
(40/173) Screening chemical composition and in vitro antioxidant and antimicrobial activities of the essential oils from Origanum syriacum L. growing in Turkey.
In the present study, essential oil from the leaves of Syrian oreganum [Origanum syriacum L. (Lauraceae)] grown in Turkish state forests of the Dortyol district, Turkey, was obtained by steam distillation. The chemical composition of oil was analysed by GC and GC-MS, and was found to contain 49.02% monoterpenes, 36.60% oxygenated monoterpenes and 12.59% sesquiterpenes. The major components are as follows: gamma-terpinene, carvacrol, p-cymene and beta-caryophyllene. Subsequently, the reducing power, antioxidant and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging activities of the essential oil were studied. The reducing power was compared with ascorbic acid, and the other activities were compared with 2,6-di-tert-butyl-4-methyl phenol (BHT, butylated hydroxytoluene). The results showed that the activities were concentration dependent. The antioxidant activities of the oil were slightly lower than those of ascorbic acid or BHT, so the oil can be considered an effective natural antioxidant. Antimicrobial activities of the essential oil from the leaves of Origanum syriacum was also determined on 16 microorganisms tested using the agar-disc diffusion method, and showed antimicrobial activity against 13 of these. (+info)