[Tuberculous bacilli resistant to cycloserine].
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Anti-Bacterial Agents↗
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Antibacterial management of infections due to gram-negative bacilli. II. Use of the teteracyclines, chloramphenicol, polymyxin B, cycloserine, and paromomycin.
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Anti-Bacterial Agents↗
Inhibitors of sphingolipid synthesis modulate interferon (IFN)-gamma-induced intercellular adhesion molecule (ICAM)-1 and human leukocyte antigen (HLA)-DR expression on cultured normal human keratinocytes: possible involvement of ceramide in biologic action of IFN-gamma.
To elucidate the participation of sphingosine and ceramide in the biologic action of cytokines on epidermal keratinocytes, we studied whether inhibitors of sphingolipid synthesis modulate interferon (IFN)-gamma-induced intercellular adhesion molecule (ICAM)-1 and human leukocyte antigen (HLA)-DR expression on cultured normal human keratinocytes. Pretreatment of keratinocytes with L-cycloserine or fumonisin B1, but not 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), significantly suppressed both ICAM-1 and HLA-DR expression induced by IFN-gamma. Because the synthesis of all kinds of sphingolipids is blocked by L-cycloserine and all except that of sphinganine by fumonisin B1, whereas PDMP inhibits the synthesis of glucosylceramide and glycosphingolipids, the result suggests the participation of ceramide and/or sphingosine in IFN-gamma-induced ICAM-1 and HLA-DR expression. Exogenous C2-ceramide reversed the effects of L-cycloserine and fumonisin B1. On the other hand, sphingosine reversed the effect of L-cycloserine, but not of fumonisin B1. These results indicate that ceramide participates in this pathway, as fumonisin B1, but not L-cycloserine, inhibits the synthesis of ceramide from sphingosine. In addition, reverse transcriptase polymerase chain reaction showed that L-cycloserine reduced the mRNA for ICAM-1, HLA-DR alpha, and HLA-DR beta induced by IFN-gamma, and C2-ceramide and sphingosine antagonized the effect of L-cycloserine. Furthermore, the degradation rate of fluorescent sphingomyelin into ceramide in keratinocytes was increased by IFN-gamma, suggesting that IFN-gamma activates sphingomyelin hydrolysis in keratinocytes. These observations suggest the possible role of ceramide in IFN-gamma-induced ICAM-1 and HLA-DR expression on keratinocytes. Ceramide may function as an endogenous modulator mediating the cytokine signals in keratinocytes.
Base Sequence↗
Role of specific aminotransferases in de novo glutamate synthesis and redox shuttling in the retina.
In this study aminotransferase inhibitors were used to determine the relative importance of different aminotransferases in providing nitrogen for de novo glutamate synthesis in the retina. Aminooxyacetate, which inhibits all aminotransferases, blocked de novo glutamate synthesis from H(14)CO(3)(-) by more than 60%. Inhibition of neuronal cytosolic branched chain amino acid transamination by gabapentin or branched chain amino acid transport by the L-system substrate analog, 2-amino-bicyclo-(2,2,1)-heptane-2-carboxylic acid, lowered total de novo synthesis of glutamate by 30%, suggesting that branched chain amino acids may account for half of the glutamate nitrogen contributed by transamination reactions. L-cycloserine, an inhibitor of alanine aminotransferase, inhibited glutamate synthesis less than 15% when added in the presence of 5 mM pyruvate but 47% in the presence of 0.2 mM pyruvate. Although high levels of pyruvate blunted the inhibitory effectiveness of L-cycloserine, the results indicate that, under physiological conditions, alanine as well as branched chain amino acids are probably the predominant sources of glutamate nitrogen in ex vivo retinas. The L-cycloserine results were also used to evaluate activity of the malate/aspartate shuttle. In this shuttle, cytosolic aspartate (synthesized in mitochondria) generates cytosolic oxaloacetate that oxidizes cytosolic NADH via malate dehydrogenase. Because L-cycloserine inhibits cytosolic but not mitochondrial aspartate aminotransferase, L-cycloserine should prevent the utilization of aspartate but not its generation, thereby increasing levels of (14)C-aspartate. Instead, L-cycloserine caused a significant decline in (14)C-aspartate. The results suggest the possibility that shuttle activity is low in retinal Müller cells. Low malate/aspartate shuttle activity may be the molecular basis for the high rate of aerobic glycolysis in retinal Müller cells.
Acetates↗
Competitive antagonists and partial agonists at the glycine modulatory site of the mouse N-methyl-D-aspartate receptor.
1. Kynurenate (Kyn), 7-chlorokynurenate (7-Cl-Kyn), 3-amino-1-hydroxypyrrolid-2-one (HA-966) and D-cycloserine are known to bind to the glycine site that modulates the N-methyl-D-aspartate (NMDA) response of vertebrate central neurones. The effects of these compounds were investigated with patch-clamp and fast-perfusion techniques on mouse cortical neurones in primary culture in an effort to establish whether they act as antagonists, partial agonists and/or inverse agonists of glycine. A fast drug application method allowed the study of both steady-state and transient responses. 2. The analysis of steady-state responses indicates that the main effects of Kyn and 7-Cl-Kyn are those expected from competitive antagonists of glycine, with a dissociation constant of 15 microM for Kyn, and of 0.3 microM for 7-Cl-Kyn. Concentration jumps indicate that at all concentrations of glycine, and in particular in the absence of added glycine, the blockade by Kyn and 7-Cl-Kyn develops at a rate which is close to the rate of dissociation of glycine from its binding site and is independent of antagonist concentration. 3. The main effects of D-cycloserine and of HA-966 are those of partial agonists of high and low efficacy, respectively. In the absence of added glycine, D-cycloserine always produced a potentiation, while HA-966 produced either a potentiation or an inhibition. This can be explained by assuming the presence of a variable level of contaminating glycine. With both D-cycloserine and HA-966, concentration jumps produced biphasic relaxations in which the onset rate of the slow component was, here again, close to the rate of dissociation of glycine from its binding site. 4. These results can be interpreted by assuming that (1) Kyn and 7-Cl-Kyn are competitive antagonists of glycine, (2) HA-966 and D-cycloserine are partial agonists, (3) in the absence of added glycine some glycine is present in the extracellular solution and (4) the response in the total absence of glycine is very small or negligible.
Action Potentials↗
Temperature-sensitive autolysis-defective mutants of Escherichia coli.
Two independently isolated temperature-sensitive autolysis-defective mutants of Escherichia coli LD5 (thi lysA dapD) were characterized. The mutants were isolated by screening the survivors of a three-step enrichment process involving sequential treatments with bactericidal concentrations of D-cycloserine, benzyl-penicillin, and D-cycloserine at 42 degrees C. Cultures of the mutants underwent autolysis during beta-lactam treatment, D-cycloserine treatment, or diaminopimelic acid deprivation at 30 degrees C. The same treatments at 42 degrees C inhibited growth but did not induce lysis of the mutants. The minimum inhibitory concentrations of selected beta-lactam antibiotics and D-cycloserine were identical for the parent and mutant strains at both 30 and 42 degrees C. Both mutants failed to form colonies at 42 degrees C, and both gave rise to spontaneous temperature-resistant revertants. The revertants exhibited the normal lytic response when treated with D-cycloserine and beta-lactams or when deprived of diaminopimelic acid at 42 degrees C. The basis for the autolysis-defective phenotype of these mutants could not be determined. However, a nonspecific in vitro assay for peptidoglycan hydrolase activity in cell-free extracts indicated that both mutants were deficient in a peptidoglycan hydrolase. Both mutations were localized to the 56- to 61-min region of the E. coli chromosome by F' complementation.
Ampicillin↗
Inhibition of staphylococcal enterotoxin B formation by cell wall blocking agents and other compounds.
Enterotoxin B formation by Staphylococcus aureus S6 was inhibited by Tween 80, oleic acid, sodium deoxycholate, penicillin, d-cycloserine, or bacitracin. Toxin formation by strain 243 was sensitive to oleic acid, sodium deoxycholate, sodium lauryl sulfate, d-cycloserine, or bacitracin. The effect of d-cycloserine was reversed by d-alanine with strain 243 but not with strain S6. Neither penicillin nor bacitracin inhibited alpha-hemolysin or coagulase activity of strain S6; however, 0.118 mumoles of d-cycloserine per ml increased the alpha-hemolysin titer more than eightfold. Pigmentation of strain 243 was reduced by oleic acid, sodium deoxycholate, or methicillin, and was completely inhibited by d-cycloserine or bacitracin. Glucose was required for the inhibition by spermine of (14)C-valine incorporation into cellular protein of strain S6. These data indicate that the cell surface may contain sites important to the synthesis of enterotoxin B.
Alanine↗
Substrate-reduction therapy enhances the benefits of bone marrow transplantation in young mice with globoid cell leukodystrophy.
Globoid cell leukodystrophy is an autosomal recessive disease with progressive demyelination caused by a deficiency of the lysosomal enzyme galactosylceramidase. Bone marrow transplantation (BMT) is a therapeutic option for patients with late-onset disease and for patients with early onset disease that had an early diagnosis owing to an affected sibling. This therapy, however, typically is not effective for early onset disease when the diagnosis occurs after several months of life. In an effort to enable a broader range of patients to benefit from BMT, we tested whether combining substrate-reduction therapy with BMT would result in a greater benefit than either treatment alone in the twitcher mouse model of globoid cell leukodystrophy. Twitcher mice treated with L-cycloserine, an inhibitor of 3-ketodyhydrosphingosine synthase, and transplanted with 50 +/- 5 x 10(6) bone marrow cells on d 10 had a mean life-span of 112 d compared with 51 d for BMT alone (p < 0.001) or L-cycloserine alone, which was previously reported to be 56 d. L-Cycloserine treatment also was initiated neonatally to determine whether it would allow for a delayed BMT to have therapeutic value. Twitcher mice given only BMT at 18 d or only a short course of L-cycloserine died at 36 and 37 d, respectively. Twitcher mice given a short course of L-cycloserine + BMT at 18 d lived to 58 d (p = 0.0006). In conclusion, substrate-reduction therapy enhanced the value of BMT in twitcher mice, suggesting that this combination strategy might benefit patients with globoid cell leukodystrophy.
Animals↗
Cell division in blue-green bacteria: stimulation of localized regions of peptidoglycan metabolism by ethanol.
D-Cycloserine was used to localize regions of active peptidoglycan metabolism as bulged, weakened areas in the lateral wall. Strain SN29 is a non-septate filamentous mutant of Agmenellum quadruplicatum and produces one to two such bulges per filament during exponential growth in the presence of D-cycloserine. The addition of ethanol to D-cycloserine inhibited filaments results in the production of many additional bulges in the lateral wall and is interpreted as evidence for the localized activation of peptidoglycan metabolism by ethanol. In the parent organism, D-cycloserine selectively inhibits cell division resulting in the formation of enlarged spindle-shaped cells. Cell separation was also affected. Chain formation was greatly reduced in septate mutants of A. quadruplicatum by growth in the presence of D-cycloserine. This was apparently due to the increase fragility of cells within the filaments.
Cell Division↗
Inhibition of the synthesis of glycosphingolipids affects the translocation of proteolipid protein to the myelin membrane.
Brain slices obtained from young rats were incubated with different radioactive precursors, in the presence and absence of L-cycloserine (an inhibitor of the synthesis of sphingosine) in order to explore the possibility that transport of proteolipids--and specifically of the major myelin proteolipid PLP--to the myelin membrane could be coupled to the transport of cerebrosides or sulfatides. At a concentration of 0.15 mM L-cycloserine, the incorporation of [3H] glycine into total proteins, proteolipid apoproteins (APL), PLP, and myelin basic proteins (MBP) of the total homogenate was unaffected by the presence of the inhibitor, whereas the incorporation of [3H] serine into glycosphingolipids decreased markedly. Under similar incubation conditions, the entry of labeled APL and of PLP into the myelin membranes in the presence of L-cycloserine decreased markedly (50%) in comparison to controls. Entry of MBP was not affected by the inhibitor. These results indicate that when synthesis of glycosphingolipids is inhibited by L-cycloserine, thus decreasing the availability of cerebrosides and sulfatides, the translocation of PLP to myelin is disrupted, suggesting that its transport through the oligodendroglial cell could be coupled to the transport of glycosphingolipids and, most probably, of sulfatides.
Animals↗
Effects of NMDA receptor modulation on hippocampal type 2 theta activity in rats.
1. The present study was designed to investigate whether pharmacological modulation of N-methyl-D-aspartate (NMDA) receptor function could modify hippocampal type 2 theta activity in the dentate gyrus of rats. 2. The effects of pre-recording administration of d-cycloserine (DCS: 1.0, 3.0 and 9.0 mg/kg, i.p.), a partial agonist at the NMDA receptor associated glycine site, and MK-801 (0.1 mg/kg, i.p.), a noncompetitive NMDA receptor antagonist, were examined in freely moving rats. 3. Using adult Wistar rats, which had recording electrodes implanted unilaterally into the hilus of dentate gyrus, we recorded five 4 sec epochs of awake-immobility-related hippocampal EEG activity bands (1-20 Hz) 40 min after d-cycloserine and 2 hr after administration of MK-801. 4. In the off-line analysis, the spectral power and the frequency at the maximal theta power were calculated. 5. D-cycloserine (1.0-9.0 mg/kg) did not affect the frequency at the maximal theta power. However, the dose of 3.0 mg/kg, though not the 1.0 or 9.0 mg/kg doses, significantly increased the spectral power of the hippocampal immobility-related EEG activity. 6. In line with the previous findings, 0.1 mg/kg MK-801 decreased both the frequency at the maximal theta power as well as the spectral power of hippocampal type 2 EEG activity. 7. The present data show a clear relationship between NMDA receptors and hippocampal type 2 theta activity and suggest that the pharmacological modulation of the receptor function, using appropriate doses of glycine binding site agonist, d-cycloserine, may be a possible means to positively modulate the immobility-related hippocampal EEG activity.
Animals↗
Interactions of cholinergic and glutamatergic neuronal systems in the functional activation of cerebral blood flow response: a PET study in unanesthetized monkeys.
The effects of somatosensory stimulation on the regional cerebral blood flow (rCBF) response were studied in unanesthetized monkeys under modulations of the glutamatergic and cholinergic systems using [15O]H2O and positron emission tomography (PET). Under a saline condition, vibrotactile stimulation elicited a significant increase in the rCBF response in the contralateral somatosensory cortex. The systemic administration of scopolamine, a muscarinic cholinergic receptor antagonist, resulted in the dose-dependent reduction of the rCBF response to the stimulation. The rCBF response abolished by scopolamine was recovered by the administration of physostigmine, a cholinesterase inhibitor in a dose-dependent manner. In addition, D-cycloserine, a partial agonist at the glycine site coupled to N-methyl-D-aspartate (NMDA) receptors, also restored the scopolamine-abolished rCBF response. The regional cerebral metabolic rate of glucose (rCMRglc) response, measured with [18F]-2-fluoro-2-deoxy-D-glucose, was not affected by the administration of scopolamine, physostigmine and/or D-cycloserine. The systemic administration of (+)-3-amino-1-hydroxy-2-pyrrolidone (HA-966), an antagonist of the glycine modulatory site on the NMDA receptors, induced the dose-dependent suppression of the rCBF response to the stimulation. The rCBF response abolished by HA-966 was restored by D-cycloserine, but not by physostigmine. The rCMRglc response was partially but significantly reduced by the administration of HA-966, and its reduction was restored by D-cycloserine, but not by physostigmine. These findings provided pharmacological evidence for an interaction between cholinergic and glutamatergic neuronal systems, the latter of which mediates the former by downstream regulation, in the functional rCBF response to somatosensory stimulation.
Animals↗
Interference of modern antibacterials with bacillus Calmette-Guerin viability.
PURPOSE: We determine the effects of modern antibacterial chemotherapeutics on bacillus Calmette-Guerin (BCG) viability, particularly those of cycloserine, which has been recommended for treating BCG induced sepsis. MATERIALS AND METHODS: The minimal inhibitory concentrations of 31 antibacterial drugs against Connaught BCG strain were determined in vitro by the radiometric BACTEC 460TB method. Minimal inhibitory concentrations were compared with the drug concentrations achievable in blood and urine to estimate systemic or intravesical susceptibility. Susceptibility testing of cycloserine was performed with Connaught, Tice and RIVM BCG strains, using the modified proportion method on Lowenstein-Jensen agar. RESULTS: Connaught BCG was susceptible to quinolones in systemic infections but resistant to beta-lactams, macrolides and some aminoglycosides. It was resistant to pyrazinamide but showed good susceptibility toward the other antituberculosis drugs tested. All 3 BCG strains analyzed were resistant to cycloserine. Most antibacterials may interfere with BCG in the bladder because of high urinary recovery. CONCLUSIONS: Antibacterial drug interference with BCG viability should be avoided during intravesical instillation therapy. In cases of severe complications quinolones rather than cycloserine may be given in addition to standard triple antituberculosis drug therapy or if one of these drugs is not tolerated. Our data may contribute toward enhancing the therapeutic safety and efficacy of intravesical BCG immunotherapy by the appropriate use of antibacterial drugs.
Antibiotics, Antitubercular↗
Effects of NMDA modulation in scopolamine dementia.
D-Cycloserine is a partial agonist at the strychnine-insensitive neuronal glycine receptor and positively modulates the N-methyl-D-aspartate (NMDA) excitatory amino acid receptor. NMDA receptors appear to be important in learning and memory, and D-cycloserine facilitates learning in rats. In man, central cholinergic blockade due to scopolamine administration impairs attention, information processing, and memory for new information, the latter secondary memory impairments resembling those shown in patients with Alzheimer's disease (AD). D-Cycloserine has been studied for its ability to counteract the cognitive decrements produced by scopolamine in young and elderly healthy volunteers. D-Cycloserine specifically antagonized the memory impairments produced by scopolamine. These findings provide evidence of NMDA receptor involvement in human memory and suggest a novel mechanism for alleviation of memory loss associated with aging and dementia.
Adolescent↗
Mycobacterium smegmatis D-Alanine Racemase Mutants Are Not Dependent on D-Alanine for Growth.
Mycobacterium smegmatis is a fast-growing nonpathogenic species particularly useful in studying basic cellular processes of relevance to pathogenic mycobacteria. This study focused on the D-alanine racemase gene (alrA), which is involved in the synthesis of D-alanine, a basic component of peptidoglycan that forms the backbone of the cell wall. M. smegmatis alrA null mutants were generated by homologous recombination using a kanamycin resistance marker for insertional inactivation. Mutants were selected on Middlebrook medium supplemented with 50 mM D-alanine and 20 microg of kanamycin per ml. These mutants were also able to grow in standard and minimal media without D-alanine, giving rise to colonies with a drier appearance and more-raised borders than the wild-type strain. The viability of the mutants and independence of D-alanine for growth indicate that inactivation of alrA does not impose an auxotrophic requirement for D-alanine, suggesting the existence of a new pathway of D-alanine biosynthesis in M. smegmatis. Biochemical analysis demonstrated the absence of any detectable D-alanine racemase activity in the mutant strains. In addition, the alrA mutants displayed hypersusceptibility to the antimycobacterial agent D-cycloserine. The MIC of D-cycloserine for the mutant strain was 2.56 microg/ml, 30-fold less than that for the wild-type strain. Furthermore, this hypersusceptibility was confirmed by the bactericidal action of D-cycloserine on broth cultures. The kinetic of killing for the mutant strain followed the same pattern as that for the wild-type strain, but at a 30-fold-lower drug concentration. This effect does not involve a change in the permeability of the cell wall by this drug and is consistent with the identification of D-alanine racemase as a target of D-cycloserine. This outcome is of importance for the design of novel antituberculosis drugs targeting peptidoglycan biosynthesis in mycobacteria.
Alanine↗
Involvement of the relA gene product and feedback inhibition in the regulation of DUP-N-acetylmuramyl-peptide synthesis in Escherichia coli.
The regulation of uridine diphosphate-N-acetylmuramyl-peptide (UDP-MurNAc-peptide) synthesis was studied by labeling Escherichia coli strains auxotrophic for lysine and diaminopimelate with [3H]diaminopimelate for 15 min under various conditions. The amounts of [3H]diaminopimelate incorporated into UDP-MurNAc-tripeptide and -pentapeptide by a stringent (rel+) strain were the same in the presence or absence of lysine. Chloramphenicol-treated rel+ cells showed a 2.8-fold increase in labeled UDP-MurNAc-pentapeptide. An isogenic relaxed (relA) strain deprived of lysine showed a 2.7-fold increase in UDP-MurNAc-pentapeptide. Thus, UDP-MurNAc-pentapeptide synthesis is regulated by the relA gene. D-Cycloserine treatment of rel+ and relA strains caused a depletion of intracellular UDP-MurNAc-pentapeptide. Labeled UDP-MurNAc-tripeptide accumulated in D-cycloserine-treated cells of the rel+ and relA strains, suggesting that UDP-MurNAc-pentapeptide is a feedback inhibitor of UDP-MurNAc-peptide synthesis. In lysine-deprived cells, D-cycloserine treatment caused 41- and 71-fold accumulations of UDP-MurNAc-tripeptide in rel+ and relA strains, respectively. A 124-fold increase in UDP-MurNAc-tripeptide occurred in lysine-deprived rel+ cells treated with both chloramphenicol and D-cycloserine. These results indicate that both the relA gene product and feedback inhibition are involved in regulating UDP-MurNAc-peptide synthesis during amino acid deprivation.
Chloramphenicol↗
Cell membrane phospholipids and their constitutent fatty acids in dividing and nondividing cells of Micrococcus lysodeikticus.
Changes occurring in the cell membrane of nondividing cells of Micrococcus lysodeikticus disIIp+ grown in the presence of the mucopeptide synthesis inhibitor D-cycloserine include (a) an increae in the relative amount of diphosphatidylglycerol with a concomitant decrease in the relative content of phosphatidylglycerol, (b) a small increase in the relative palmitic acid content of phosphatidylinositol, and (c) leakage of membrane components into the growth medium. Growth of the organism in the presence of both D-cycloserine and D-alanine (which prevents the effects of D-cycloserine on cell division and mucopeptide synthesis) prevents the above changes in the cell membrane, demonstrating that secondary damage to the cell membrane can occur as a rsult of inhibition in mucopeptide synthesis. Growth of the organism in the presence of D-cycloserine and pantoyl lactone prevents the leakage of membrne components and cell division inhibition. Possible relationships of these changes to cell division are discussed.
Alanine↗
Sphingolipids as mediators of effects of platelet-derived growth factor in vascular smooth muscle cells.
The role of sphingolipids in mediating the action of platelet-derived growth factor (PDGF) has been investigated in the vascular smooth muscle-derived A7r5 cell line. L-Cycloserine (2 mM), an inhibitor of sphingolipid synthesis, caused time-dependent inhibition of [3H]serine incorporation into [3H]sphingomyelin in A7r5 cells. PDGF-AB (10 ng/ml), PDGF-BB (10 ng/ml), or sphingosine (10 microM) independently stimulated [3H]thymidine incorporation into DNA in A7r5 cells. L-Cycloserine (2 mM) inhibited stimulation of DNA synthesis by both PDGF-AB and PDGF-BB. L-Cycloserine (2 mM, 16 h) did not affect the ability of PDGF or sphingosine to increase intracellular free calcium ([Ca2+]i) in A7r5 cells loaded with the fluorescent indicator fura 2. Measurement of adenine nucleotide levels in A7r5 cell extracts by reverse-phase high-performance liquid chromatography indicated that treatment with L-cycloserine did not adversely affect cellular metabolism. To determine directly whether PDGF activates sphingolipid metabolism, A7r5 cells were labeled with [3H]serine for 48 h and then treated with PDGF-AB (10 ng/ml) for 1 h. Sphingolipids were separated by thin-layer chromatography and quantified by liquid scintillation counting. PDGF-AB stimulated an increase in [3H]sphingosine from 25.5 +/- 3.0 to 37.5 +/- 4.1 counts.min-1 (cpm).micrograms protein-1 and a concomitant decrease in [3H]ceramide from 24.3 +/- 3.2 to 18.5 +/- 2.9 cpm/micrograms protein. These data suggest that the PDGF-stimulated increase in [Ca2+]i is not sufficient for induction of DNA synthesis and that mitogenic effects of PDGF in vascular smooth muscle cells are mediated by sphingolipid metabolism.
Adenine Nucleotides↗