Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nafcillin, a semisynthetic penicillin effective against penicillinase-producing staphylococci, is eliminated largely in man via the liver. This study assessed the effect of cirrhosis and extrahepatic biliary obstruction in man on the pharmacokinetics of nafcillin. The plasma clearance of nafcillin controls was 583 +/- 144.2 ml per min (mean +/- SD) and fell strikingly to 291 +/- 147.6 and 163 +/- 56.3 ml per min in patients with cirrhosis and extrahepatic obstruction, respectively (P less than 0.001). In the latter two groups nafcillin excreted in urine increased from about 30 to 50% of administered dose (P less than 0.02), suggesting that renal disease superimposed on hepatic disease would further decrease over-all nafcillin clearance. The depression of nafcillin clearance with hepatobiliary disease did not correlate with any conventional liver laboratory test. The initial volume of distribution of nafcillin (V1) was unaltered but at steady state (Vd()) there was a significant reduction in the distribution volume in the patients with liver disease. Accordingly, the impairment in drug elimination, as assessed by its clearance from plasma, was underestimated by the prolongation of the nafcillin elimination half-life (t1/2(beta)) which was 1.02 +/- 0.20 hr in controls, and 1.23 +/- 0.31 (P greater than 0.05) and 1.73 +/- 0.44 hr (P less than 0.03), respectively, in patients with cirrhosis and extrahepatic obstruction.
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PMID:Disposition of nafcillin in patients with cirrhosis and extrahepatic biliary obstruction. 91 79

The crystal structure of a class A beta-lactamase from Staphylococcus aureus PC1 has been refined at 2.0 A resolution. The resulting crystallographic R-factor (R = sigma h parallel Fo[-]Fc parallel/sigma h[Fo], where [Fo] and [Fc] are the observed and calculated structure factor amplitudes, respectively), is 0.163 for the 17,547 reflections with I greater than or equal to 2 sigma (I) within the 8.0 A to 2.0 A resolution range. The molecule consists of two closely associated domains. One domain is formed by a five-stranded antiparallel beta-sheet with three helices packing against a face of the sheet. The second domain is formed mostly by helices that pack against the second face of the sheet. The active site is located in the interface between the two domains, and many of the residues that form it are conserved in all known sequences of class A beta-lactamases. Similar to the serine proteases, an oxyanion hole is implicated in catalysis. It is formed by two main-chain nitrogen atoms, that of the catalytic seryl residue, Ser70, and that of Gln237 on an edge beta-strand of the major beta-sheet. Ser70 is interacting with another conserved seryl residue, Ser130, located between the two ammonium groups of the functionally important lysine residues, Lys73 and Lys234. Such intricate interactions point to a possible catalytic role for this second seryl residue. Another key catalytic residue is Glu166. There are several unusual structural features associated with the active site. (1) A cis peptide bond has been identified between the catalytic Glu166 and Ile167. (2) Ala69 and Leu220 have strained phi, psi dihedral angles making close contacts that restrict the conformation of the active site beta-strand involved in the formation of the oxyanion hole. (3) A buried aspartate residue, the conserved Asp233, is located next to the active site Lys234. It is interacting with another buried aspartyl residue, Asp246. An internal solvent molecule is also involved, but the rest of its interactions with the protein indicate it is not a cation. (4) Another conserved aspartyl residue that is desolvated is Asp131, adjacent to Ser130. Its charge is stabilized by interactions with four main-chain nitrogen atoms. (5) An internal cavity underneath the active site depression is filled with six solvent molecules. This, and an adjacent cavity occupied by three solvent molecules partially separate the omega-loop associated with the active site from the rest of the protein.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Refined crystal structure of beta-lactamase from Staphylococcus aureus PC1 at 2.0 A resolution. 200 20

beta-lactamases are enzymes that protect bacteria from the lethal effects of beta-lactam antibiotics, and are therefore of considerable clinical importance. The crystal structure of beta-lactamase from the Gram-positive bacterium Staphylococcus aureus PC1 has been determined at 2.5 angstrom resolution. It reveals a molecule of novel topology, made up of two closely associated domains. The active site is located at the interface between the domains, with the key catalytic residue Ser70 at the amino terminus of a buried helix. Examination of the disposition of the functionally important residues within the active site depression leads to a model for the binding of a substrate and a functional analogy to the serine proteases. The unusual topology of the secondary structure units is relevant to questions concerning the evolutionary relation to the beta-lactam target enzymes of the bacterial cell wall.
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PMID:Bacterial resistance to beta-lactam antibiotics: crystal structure of beta-lactamase from Staphylococcus aureus PC1 at 2.5 A resolution. 310 25

Depression of beta-lactamases in certain non-fastidious Gram-negative bacilli has been responsible for (i) the rapid development of resistance to a variety of beta-lactam antibiotics and (ii) antagonism between beta-lactam antibiotics. Therefore, the effects of a variety of inhibitors of macro-molecular synthesis on derepression of beta-lactamase were investigated with four strains each of enterobacter and Pseudomonas aeruginosa. When tested at concentrations that were not inhibitory to growth, clindamycin was the most effective inhibitor of derepression of beta-lactamases in some of the strains examined. In one enterobacter isolate, clindamycin completely prevented derepression of beta-lactamases. This effect was highly specific as clindamycin did not influence constitutive beta-lactamase or depression of other inducible enzymes in this same strain. These results suggest that clindamycin may selectively inhibit synthesis of beta-lactamase under repressor control in some bacteria without affecting synthesis of other proteins or replication. Such selective inhibition may provide a new approach for the enhancement of the antibacterial activity of certain beta-lactam antibiotics.
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PMID:Effects of clindamycin on derepression of beta-lactamases in gram-negative bacteria. 641 3

Arg mutants, isolated from Streptomyces lavendulae at unusually high frequencies, showed several phenotypic characteristics. The characteristics common to all arg mutants include: (1) repression of beta-lactamase production, (2) inhibition of aerial mycelium formation, (3) development of acid pH, (4) low saturation density of growth in liquid culture, (5) a decrease in antibiotic production, (6) an increase in sensitivity to benzylpenicillin and (7) a decrease in production of pigment. These results suggest that the arg mutation concomitantly caused the depression of secondary metabolism in S. lavendulae.
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PMID:Multiple effects induced by unstable mutation in Streptomyces lavendulae. 696 67

Twenty-nine British and Irish hospitals each collected up to 300 bacterial isolates from in-patients. The organisms were identified by an appropriate API system or, for staphylococci, by their Gram and coagulase reactions. Disc susceptibility tests were performed. Isolates that gave zones < or = 25 mm to piperacillin/tazobactam (75 micrograms + 10 micrograms) discs were sent to a central laboratory for re-examination and determination of MIC, together with a sample of the more susceptible organisms. Results were evaluated for 6724 isolates. Over 95% of the isolates of Escherichia coli, klebsiellae, Proteus mirabilis, Pseudomonas aeruginosa, Haemophilus, Moraxella and Bacteriodes, spp. streptococci, pneumococci and Enterococcus faecalis were susceptible to piperacillin/tazobactam (defined as giving a zone > or = 22 mm to a 75 micrograms + 10 micrograms disc), as were 86% of Acinetobacter spp. and 82% of the Citrobacter, Enterobacter, Morganella and Serratia group. Tazobactam particularly extended the activity of piperacillin against E. coli isolates (96% susceptible cf. 61% to piperacillin alone) klebsiellae (95% cf. 70%), P. mirabilis (99% cf. 86%), and Acinetobacter spp. (86% cf. 53%). Occasional (18%) resistance in Enterobacter, Serratia and Citrobacger spp. was probably caused by stable depression of Class I beta-lactamases, which are inhibited poorly by tazobactam. High resistance frequencies (> 25%) were found for Enterococcus faecium and Xanthomonas maltophilia. Tazobactam potentiated piperacillin against beta-lactamase-producing methicillin-susceptible Staphylococcus aureus, but the mode inhibition zone of piperacillin/tazobactam discs was only 26 mm, compared to 38 mm for beta-lactamase-negative isolates. Nevertheless, fewer than 5% of the enzyme producers appeared resistant to 8 + 4 mg/L piperacillin/tazobactam in MIC tests. Similar behaviour was noted for coagulase-negative staphylococci. Amongst the eleven comparator drugs, ceftazidime, gentamicin and ciprofloxacin were as active as piperacillin/tazobactam against most enterobacteria. However, Acinetobacter and Bacteroides spp. and enterococci were resistant to ceftazidime, and Bacteroides spp., enterococci, pneumococci and other streptococci were inherently resistant to ciprofloxacin and gentamicin. Cefuroxime, ampicillin and co-amoxiclav had narrower spectra. Only imipenem showed a consistently wider spectrum and lower frequency of resistance than piperacillin/tazobactam.
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PMID:Multicentre survey of the comparative in-vitro activity of piperacillin/tazobactam against bacteria from hospitalized patients in the British Isles. 822 27

Infections in immunocompromised patients and in patients with indwelling prosthetic devices are often caused by hospital strains of Staphylococcus epidermidis resistant to methicillin. Tests for the detection of methicillin resistance, indicating resistance to all beta-lactam antibiotics, were evaluated in order to define a suitable screening test. A broth tube breakpoint test with a large inoculum, 10(7) colony forming units (cfu), gave the highest recovery of resistant strains. False resistance due to hyperproduction of beta-lactamase was excluded. The results correlated completely with the detection of the resistance gene, mecA, by the polymerase chain reaction. In 2/3 of the resistant strains tested the expression of the methicillin resistance was heterogeneous, only one cell in 10(2) to 10(4) expressed the resistance within 72 h in both. In broth screening tests an inoculum of at least 10(6) cfu therefore was required to detect all resistant strains within 24 h. Using agar dilution, 48 h incubation must be considered. In disc diffusion tests reliable results were obtained after only 16 h of incubation when discs containing cephradine 5 and 30 micrograms, oxacillin 1 microgram or cephalexin 30 micrograms were used, and the first disc is recommended for routine work. The epidemiology of S. epidermidis strains resistant to ciprofloxacin and/or gentamicin was studied in an isolation unit for patients undergoing bone marrow transplantation. Antibiograms and plasmids were used for typing and 31 such strains were found. Of 54 staff members 10 were colonized in the nares only, two in the nares and perineum and one in the nares and stool. In ambient air and on the clothes of staff a few of the strains predominated quantitatively. These strains colonized the skin of some of the patients who seemed to be the main dispersers. Possible routes of cross-infection were indirect contact transfer via the hands and clothes of staff (82% of the clothes were contaminated), and direct as well as indirect airborne transmission. To study the effects of chlorhexidine on skin bacteria, ten nurses washed one arm with chlorhexidine-detergent every morning for 3 weeks; the other arm served as control. The depression of the normal skin flora did not lead to a colonization with more antibiotic-resistant hospital strains. During the wash period the counts of antibiotic-resistant S. epidermidis on the treated arms were significantly reduced compared with the control arms, as also were the number of different strains.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Staphylococcus epidermidis--hospital epidemiology and the detection of methicillin resistance. 830 17

The recent data concerning antibiotic resistance of the enterobacteria isolated in Greek hospitals are reviewed. A variety of mechanisms of resistance, clustered in most of the cases, was observed. Epidemics of plasmids were responsible for dissemination of third-generation cephalosporins, aminoglycosides, and trimethoprim resistance among Klebsiella pneumoniae and, to a lesser extent, Escherichia coli isolates. Stable depression of the expression of chromosomal cephalosporinase is the main cause of resistance to third-generation cephalosporins observed at high frequencies in Enterobacter spp. strains.
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PMID:Prevalent mechanisms of resistance among common enterobacterial isolates in Greek hospitals. 915 5

The structure of class A beta-lactamases contains an omega-loop associated with the active site, which carries a key catalytic residue, Glu166. A 16-residue omega-loop deletion mutant of beta-lactamase from Staphylococcus aureus PC1, encompassing residues 163-178, was produced in order to examine the functional and structural role of the loop. The crystal structure was determined and refined at 2.3 A, and the kinetics of the mutant enzyme was characterized with a variety of beta-lactam antibiotics. In general, the wild-type beta-lactamase hydrolyzes penicillin compounds better than cephalosporins. In contrast, the deletion of the omega-loop led to a variant enzyme that acts only on cephalosporins, including third generation compounds. Kinetic measurements and electrospray mass spectrometry revealed that the first and third generation cephalosporins form stable acyl-enzyme complexes, except for the chromogenic cephalosporin, nitrocefin, which after acylating the enzyme undergoes hydrolysis at a 1000-fold slower rate than that with wild-type beta-lactamase. Hydrolysis of the acyl-enzyme adducts is prevented because the deletion of the omega-loop eliminates the deacylation apparatus comprising Glu166 and its associated nucleophilic water site. The crystal structure reveals that while the overall fold of the mutant enzyme is similar to that of the native beta-lactamase, local adjustments in the vicinity of the missing loop occurred. The altered beta-lactam specificity is attributed to these structural changes. In the native structure, the omega-loop restricts the conformation of a beta-strand at the edge of the active site depression. Removal of the loop provides the beta-strand with a new degree of conformational flexibility, such that it is displaced inward toward the active site space. Modeled Michaelis complexes with benzylpenicillin and cephaloridine show that the perturbed conformation of the beta-strand is inconsistent with penicillin binding because of steric clashes between the beta-lactam side chain substituent and the beta-strand. In contrast, no clashes occur upon cephalosporin binding. Recognition of third generation cephalosporins is possible because the bulky side chain substituents of the beta-lactam ring typical of these compounds can be accommodated in the space freed by the deletion of the omega-loop.
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PMID:Role of the omega-loop in the activity, substrate specificity, and structure of class A beta-lactamase. 952 48

Neurotrophins are a family of secreted proteins that play an important role in the development, differentiation, and survival of neurons. Studies also suggest that aberrant neurotrophin signaling may play a role in processes underlying disease states such as schizophrenia, Alzheimer's disease, and depression. Whereas the development of agents that selectively stimulate neurotrophin signaling has proven to be difficult, compounds have been identified that potentiate neurotrophin 3 (NT-3)-mediated activation of trk A. In the present studies, we extend those initial observations to identify compounds that also potentiate NT-3-mediated activation of trk B. Compound potentiation of NT-3 was observed using several readouts of transfected and endogenous trk receptor activity, including trk receptor phosphorylation, mitogen-activated protein kinase phosphorylation, reporter assay activity (beta-lactamase and luciferase), cell survival and neurite extension assays. Studies using chimeric trk receptors demonstrated that the extracellular domain is essential for compound potentiation and rule out interaction with intracellular signaling molecules as a mechanism of compound activity. Thus, the present studies demonstrate that trk B receptor activity can be potentiated by small-molecule compounds via the extracellular domain of the receptor and provide reagents for further evaluating the role of NT-3-mediated trk A and trk B activity in vivo.
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PMID:Identification and characterization of compounds that potentiate NT-3-mediated Trk receptor activity. 1639 50


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