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At least 991 records · Page 55Linked to original sources
PubMed1973

Lividomycin resistance in staphylococci by enzymatic phosphorylation.

Enzymatic inactivation of lividomycin (LV) was attempted with nine clinical isolates of staphylococci including LV-susceptible and -resistant strains. LV inactivation and the incorporation into LV of (32)P from gamma-(32)P-adenosine triphosphate were demonstrated in the presence of cell-free extracts from LV-resistant strains but not from LV-susceptible ones. The enzyme was purified approximately 82-fold from a resistant Staphylococcus aureus strain by means of ammonium sulfate fractionation and column chromatography. Some properties of the partially purified LV-phosphorylating enzyme were quite similar to those of an enzyme from Escherichia coli carrying an R factor conferring LV resistance, and the phosphorylated product of the drug was also found to be identical with that produced by E. coli carrying an R factor, i.e., 5''-phosphoryl-LV.

Adenosine Triphosphate↗
PubMed1973

Mode of action of lividomycin on protein synthesis in Escherichia coli.

Lividomycin specifically inhibited bacterial protein synthesis and had codon misreading activity. Lividomycin, moreover, stimulated the binding of aminoacyl-transfer ribonucleic acid to ribosomes, but did not show any significant effects on the formation of aminoacyl-transfer ribonucleic acid and the puromycin reaction.

Amino Acids↗
PubMed1973

Structure-activity relationships among the aminoglycoside antibiotics: role of hydroxyl and amino groups.

The close structural similarity of several of the deoxystreptamine-containing aminoglycoside antibiotics (gentamicins, neomycins, kanamycins, tobramycin) and the recent isolation of enzymatically N-acetylated aminoglycosides have permitted a systematic comparison of the structure-activity relationships in this group of antibiotics. The number and location of amino groups on the hexoses and the site of attachment of the other rings to deoxystreptamine have been shown to exert a profound effect on the ability of these compounds to inhibit or to cause misreading of polypeptide synthesis in vitro. The conclusions allow certain predictions to be made concerning the interaction of these compounds with the bacterial ribosome.

Aminoglycosides↗
PubMed1997

Pharmacokinetics of intramuscularly administered aminosidine in healthy subjects.

Aminosidine is an older, broad-spectrum aminoglycoside antibiotic that has been shown to be effective in in vitro and animal models against multiple-drug-resistant tuberculosis and the Mycobacterium avium complex. The objective of this randomized, parallel trial was to characterize the single-dose pharmacokinetics of aminosidine sulfate in healthy subjects (eight males, eight females). Sixteen adults (mean [+/- standard deviation] age, 27.6 +/- 5.6 years) were randomly allocated to receive a single, intramuscular aminosidine sulfate injection at a dose of 12 or 15 mg/kg of body weight. Serial plasma and urine samples were collected over a 24-h period and used to determine aminosidine concentrations by high-performance liquid chromatographic assay. A one-compartment model with first-order input, first-order output, and a lag time (Tlag) and with a weighting factor of 1/y2 best described the data. Compartmental and noncompartmental pharmacokinetic parameters were estimated with the microcomputer program WinNonlin. One subject was not included (15-mg/kg group) because of the lack of sampling time data. On average, subjects attained peak concentrations of 22.4 +/- 3.2 microg/ml at 1.34 +/- 0.45 h. All subjects had plasma aminosidine concentrations below 2 microg/ml at 12 h, and all but two subjects (one in each dosing group) had undetectable plasma aminosidine concentrations at 24 h. The dose-adjusted area under the concentration-time curve from 0 h to infinity of aminosidine was identical for the 12- and 15-mg/kg groups (9.29 +/- 1.5 versus 9.29 +/- 2.2 microg x h/ml per mg/kg; P = 0.998). Similarly, no significant differences (P > 0.05) were observed between dosing groups for peak aminosidine concentration in plasma, time to peak aminosidine concentration in plasma, Tlag, apparent clearance, renal clearance, elimination rate constant, and elimination half-life. A significant difference was observed for the volume of distribution (0.35 versus 0.41 liters/kg; P = 0.037) between the 12 and 15 mg/kg dosing groups. Now that comparable pharmacokinetic profiles between dosing groups have been demonstrated, therapeutic equivalency testing via in vitro pharmacokinetic and pharmacodynamic modelling and randomized clinical trials in humans should be conducted.

Adult↗
PubMed1974

Phosphorylation of kanamycin, lividomycin A, amd butirosin B by Providencia stuartii.

The isolation of Providencia stuartii resistant to multiple aminoglycoside antibiotics prompted an investigation into the mechanism of their resistance. Crude enzyme extracts of a strain of P. stuartii inactivated kanamycin, lividomycin A, and butirosin B in the presence of adenosine 5'-triphosphate (ATP), as measured by a microbiological assay. The occurrence of inhibitory concentrations of 500 mug or greater per ml against kanamycin, lividomycin A, and butirosin B, coupled with the inactivation of these antibiotics in the presence of ATP, suggested enzymatic phosphorylation. This was documented by the transfer of the gamma-phosphate of [gamma-(32)P]ATP. In contrast, the inability to inactivate gentamicin or tobramycin by the crude enzyme extracts in the presence of ATP suggests another enzymatic mechanism of resistance for these antibiotics, such as adenylation or acetylation. Of importance is the fact that amikacin, a semisynthetic analogue of kanamycin A which is resistant to inactivation by most resistance transfer factor enzymes, was found to inhibit the growth of P. stuartii at low concentrations.

Aminoglycosides↗
PubMed2003

Sfp1 plays a key role in yeast ribosome biogenesis.

Sfp1, an unusual zinc finger protein, was previously identified as a gene that, when overexpressed, imparted a nuclear localization defect. sfp1 cells have a reduced size and a slow growth phenotype. In this study we show that SFP1 plays a role in ribosome biogenesis. An sfp1 strain is hypersensitive to drugs that inhibit translational machinery. sfp1 strains also have defects in global translation as well as defects in rRNA processing and 60S ribosomal subunit export. Microarray analysis has previously shown that ectopically expressed SFP1 induces the transcription of a large subset of genes involved in ribosome biogenesis. Many of these induced genes contain conserved promoter elements (RRPE and PAC). Our results show that activation of transcription from a reporter construct containing two RRPE sites flanking a single PAC element is SFP1 dependent. However, we have been unable to detect direct binding of the protein to these elements. This suggests that regulation of genes containing RRPEs is dependent upon Sfp1 but that Sfp1 may not directly bind to these conserved promoter elements; rather, activation may occur through an indirect mechanism.

Active Transport, Cell Nucleus↗
PubMed1975

"Killer" character does not influence the transmission of mitochondrial genes in Saccharomyces cerevisiae.

Three cytoplasmic genetic elements have been shown to be separate from mitochondrial deoxyribonucleic acid (DNA), [rho], in Saccharomyces cerevisiae: the killer character [k], omicron-DNA, and psi [psi]. Griffiths has suggested genetic interactions between [VENR] and [TETR] mutants possibly located on omicron-DNA and mitochondrial genetic markers, but possible interactions between the best characterized of the three, the killer character, and mitochondrial DNA have not been investigated. To test this we isolated cycloheximide-induced nonkiller segregants (NKS) of killer cells with suitable genetic markers and mated them in [k] x [k], [k] x [k], and (NKS) x (NKS) combinations. No differences in quantitative mitochondrial marker transmission between these groups were found in crosses illustrating the mitochondrial phenomena of bias, polarity, and suppressiveness. Our studies show that no intercellular interactions between [k] and (NKS) cells influence mitochondrial transmission genetics. Intracellular interactions between the smaller double-stranded ribonucleic acid of [k] and mitochondrial DNA also were not detected.

Chloramphenicol↗
PubMed1992

Gene products that promote mRNA turnover in Saccharomyces cerevisiae.

We showed previously that the increased rate of mRNA turnover associated with premature translational termination in the yeast Saccharomyces cerevisiae requires a functional UPF1 gene product. In this study, we show that the UPF1 gene codes for a 109-kDa primary translation product whose function is not essential for growth. The protein contains a potential zinc-dependent nucleic acid-binding domain and a nucleoside triphosphate-binding domain. A 300-amino-acid segment of the UPF1 protein is 36% identical to a segment of the yeast SEN1 protein, which is required for endonucleolytic processing of intron-containing pre-tRNAs. The same region is 32% identical to a segment of Mov-10, a mouse protein of unknown function. Dominant-negative upf1 mutations were isolated following in vitro mutagenesis of a plasmid containing the UPF1 gene. They mapped exclusively at conserved positions within the sequence element common to all three proteins, whereas the recessive upf1-2 mutation maps outside this region. The clustering of dominant-negative mutations suggests the presence of a functional domain in UPF1 that may be shared by all three proteins. We also identified upf mutations in three other genes designated UPF2, UPF3, and UPF4. When alleles of each gene were screened for effects on mRNA accumulation, we found that the recessive mutation upf3-1 causes increased accumulation of mRNA containing a premature stop codon. When mRNA half-lives were measured, we found that excess mRNA accumulation was due to mRNA stabilization. On the basis of these results, we suggest that the products of at least two genes, UPF1 and UPF3, are responsible for the accelerated rate of mRNA decay associated with premature translational termination.

Amino Acid Sequence↗
PubMed1999

NMD3 encodes an essential cytoplasmic protein required for stable 60S ribosomal subunits in Saccharomyces cerevisiae.

A mutation in NMD3 was found to be lethal in the absence of XRN1, which encodes the major cytoplasmic exoribonuclease responsible for mRNA turnover. Molecular genetic analysis of NMD3 revealed that it is an essential gene required for stable 60S ribosomal subunits. Cells bearing a temperature-sensitive allele of NMD3 had decreased levels of 60S subunits at the nonpermissive temperature which resulted in the formation of half-mer polysomes. Pulse-chase analysis of rRNA biogenesis indicated that 25S rRNA was made and processed with kinetics similar to wild-type kinetics. However, the mature RNA was rapidly degraded, with a half-life of 4 min. Nmd3p fractionated as a cytoplasmic protein and sedimented in the position of free 60S subunits in sucrose gradients. These results suggest that Nmd3p is a cytoplasmic factor required for a late cytoplasmic assembly step of the 60S subunit but is not a ribosomal protein. Putative orthologs of Nmd3p exist in Drosophila, in nematodes, and in archaebacteria but not in eubacteria. The Nmd3 protein sequence does not contain readily recognizable motifs of known function. However, these proteins all have an amino-terminal domain containing four repeats of Cx2C, reminiscent of zinc-binding proteins, implicated in nucleic acid binding or protein oligomerization.

Amino Acid Sequence↗
PubMed2001

Absence of Dbp2p alters both nonsense-mediated mRNA decay and rRNA processing.

Dbp2p, a member of the large family of DEAD-box proteins and a yeast homolog of human p68, was shown to interact with Upf1p, an essential component of the nonsense-mediated mRNA decay pathway. Dbp2p:Upf1p interaction occurs within a large conserved region in the middle of Upf1p that is largely distinct from its Nmd2p and Sup35/45p interaction domains. Deletion of DBP2, or point mutations within its highly conserved DEAD-box motifs, increased the abundance of nonsense-containing transcripts, leading us to conclude that Dbp2p also functions in the nonsense-mediated mRNA decay pathway. Dbp2p, like Upf1p, acts before or at decapping, is predominantly cytoplasmic, and associates with polyribosomes. Interestingly, Dbp2p also plays an important role in rRNA processing. In dbp2Delta cells, polyribosome profiles are deficient in free 60S subunits and the mature 25S rRNA is greatly reduced. The ribosome biogenesis phenotype, but not the mRNA decay function, of dbp2Delta cells can be complemented by the human p68 gene. We propose a unifying model in which Dbp2p affects both nonsense-mediated mRNA decay and rRNA processing by altering rRNA structure, allowing specific processing events in one instance and facilitating dissociation of the translation termination complex in the other.

Blotting, Northern↗
PubMed1970

Sensitivity of Hartmannella (Acanthamoeba) to 5-fluorocytosine, hydroxystilbamidine, and other substances.

The effect of 24 anti-amoebic and other chemotherapeutic compounds on six strains of hartmannellid amoebae was studied by tissue culture, agar diffusion, and liquid axenic culture. Of the recognized anti-amoebic compounds only one inhibited growth of the amoebae, which were remarkable for their resistance. Two compounds, hydroxystilbamidine isethionate and 5-fluorocytosine, showed some amoebicidal activity while some others were inhibitory.

Agar↗