PubMed Health⌕ Search

Biomedical subjects

F Le Goffic

Publications and source records attributed to F Le Goffic.

At least 37 records · Page 2Linked to original sources
PubMed1986

(1-Amino-2-propenyl) phosphonic acid, an inhibitor of alanine racemase and D-alanine:D-alanine ligase.

DL-(1-Amino-2-propenyl)phosphonic acid was synthesized through the sequential oxidation, sulfoxide elimination, and deprotection of diphenyl [1-[(benzyloxycarbonyl)amino]-3-(phenylthio)propyl] phosphonate. This analogue of vinylglycine is a strong inhibitor of the alanine racemases from Pseudomonas aeruginosa and Streptococcus faecalis and of the D-Ala:D-Ala ligase from this latter species. This molecule is ineffective against the whole bacterial cells. Unlike vinylglycine, this unsaturated phosphonate does not inhibit the following mammalian enzymes: aspartate aminotransferase, alanine aminotransferase, D-amino acid oxidase, which indicates its specificity. Thus, its incorporation in a peptide structure could induce interesting antimicrobial properties.

Alanine Racemase↗
PubMed1986

The lysine pathway as a target for a new genera of synthetic antibacterial antibiotics?

Unsaturated analogues of diaminopimelic acid have been synthesized. The amino acids were designed so that they would be reversible or irreversible inhibitors of both of the two last enzymes of the lysine pathway. The compounds were tested with meso-diaminopimelate decarboxylase. trans-3,4-Didehydrodiaminopimelic acid (2) was found to be the most potent inhibitor. The antibacterial activities did not correlate with enzyme inhibiting activities. 4-Methylenediaminopimelic acid 4 showed strong antibacterial properties. It is suggested that L,L-diaminopimelate epimerase could be the target enzyme.

Amino Acid Isomerases↗
PubMed1986

Transport and hydrolysis of peptides in Saccharomyces cerevisiae.

The transport and hydrolysis of several radioactive di- and tripeptides in Saccharomyces cerevisiae was studied. A peptide-transport-deficient mutant isolated on the basis of its resistance to nikkomycin Z lost most of its capacity to take up di- and tripeptides. The transport kinetics of [14C]methionylglycine, [14C]methionylsarcosine and [3H]nikkomycin Z indicated that peptide transport is not dependent on intracellular hydrolysis. Intact cells had some peptidase activity towards methionylsarcosine but not towards nikkomycin Z. The relationship between this activity and peptide transport is discussed.

Aminoglycosides↗
PubMed1986

Studies on pristinamycin synergism in Staphylococcus aureus.

Binding experiments were performed with both components of the pristinamycin complex (pristinamycin IA (PIA) and pristinamycin IIA (PIIA] using ribosomes from sensitive and resistant Staphylococcus aureus. Fluorescence polarization was used to measure PIA binding. The results obtained show a direct correlation between inhibition, synergy and the enhancement of the affinity of PIA for its receptor in the presence of PIIA. The uptake of PIA by intact cells seems to be directly correlated with affinity between PIA and ribosomes, a phenomenon which is probably shared with the macrolide antibiotics.

Anti-Bacterial Agents↗
PubMed1986

Irreversible binding of pristinamycin IIA (streptogramin A) to ribosomes explains its "lasting damage" effect.

In vitro and in vivo studies are presented to test the hypothesis that the synergistic action of the pristinamycins is not due to a catalytic effect of pristinamycin IIA (PIIA) on the bacterial ribosome. We demonstrate that there is a proportionality between the quantity of PIIA bound on the ribosome and pristinamycin IA (PIA) retained by it. Moreover in vitro and in vivo experiments correlated to biological effects (growth and protein synthesis) demonstrate that pristinamycin IIA is tightly bound on 70S ribosome, which satisfactory explains the so called "lasting damage effect".

Anti-Bacterial Agents↗
PubMed1986

Effects of cations, polyamines and other aminoglycosides on gentamicin C2. Binding to ribosomes from sensitive and resistant Escherichia coli strains.

Gentamicin C2 interacts cooperatively with ribosomes from a sensitive Escherichia coli strain in a multiphasic way with several classes of sites. It is shown that this binding is highly-dependent on Mg++ and natural endogenous polyamine concentrations. The differences observed between ribosomes from sensitive and resistant strains may be explained by the absence of specific cooperative gentamicin interactions with resistant ribosomes. The effects of other aminoglycoside antibiotics are discussed in terms of structure-activity relationships.

Aminoglycosides↗
PubMed1985

About the specificity of photoinduced affinity labeling of Escherichia coli ribosomes by dihydrorosaramicin, a macrolide related to erythromycin.

Photoactivation of the [3H]dihydrorosaramicin chromophore at a wavelength above 300 nm allows the covalent attachment of the macrolide antibiotic to the bacterial ribosome. Bidimensional electrophoresis shows that the radioactivity is mainly associated with proteins L1, L5, L6, L15, L18, L19, S1, S3, S4, S5 and S9. When photoincorporation of the drug is conducted in the presence of puromycin as effector of [3H]dihydrorosaramicin-binding sites, a decrease in the labeling of most proteins is observed, except for L18 and L19, which are radiolabeled to a larger extent. These results allow us to speculate that L18 and L19 belong to the high-affinity binding site of rosaramicin antibiotic.

Affinity Labels↗
PubMed1985

Mechanism of action of gentamicin components. Characteristics of their binding to Escherichia coli ribosomes.

The binding of gentamicin (Gm) to Escherichia coli ribosomes and ribosomal subunits has been studied. By means of equilibrium dialysis and of statistical interpretation of the data it was found that [3H]gentamicin C2 and 6'-N-[3H]methylgentamicin C1a interact with three classes of sites on tight-coupled 70-S species: a first class concerning the tight and non-cooperative interaction with one drug molecule (Kd = 0.6 microM), a second class in which about five Gm molecules bind cooperatively (mean Kd = 10 microM), and a third class of very high capacity in which up to 70 drug molecules may interact. The extreme cooperativity of the third class of sites induces such an increase in the affinity for Gm that it may allow the shift of molecules already bound from high-affinity sites towards lower-affinity sites. The alteration of a ribosomal protein, L6, in a gentamicin-resistant mutant of E. coli abolished the multiclass and the cooperative aspects of ribosomes--gentamicin interaction. The large ribosomal subunits from E. coli MRE 600 strain interact cooperatively with Gm, whereas 50-S particles from the resistant mutant bind the drug in a diffuse way with high capacity and low affinity. The small subunits from both strains behave identically towards Gm. A good correlation is observed in comparing the gentamicin concentrations capable of saturating the different ribosomal classes of sites with concentrations inducing its multiphasic effects on protein synthesis.

Drug Resistance, Microbial↗
PubMed1985

Structure activity relationships in lincosamide and streptogramin antibiotics.

Lincomycin is a 6-amino, 6-deoxy-octopyraninose with strong antibiotic activity. To maintain or enhance this activity, one must have the configuration of the first five asymmetric carbons of the sugar residue with the thioglycolic moiety in the alpha-position. The nitrogen on carbon 6 with the R configuration is also a prerequisite for the activity. Substitutions at the level of C-7 as well as the pyrolidine moiety can dramatically enhance this activity. The streptogramin group is composed of a wide variety of structures which can be classified into two subgroups. Group A or M is composed of polyunsaturated cyclic peptolides, e.g. pristinamycin IIA; group B or S is composed of cyclic hexadepsipeptides. Separately, these molecules have a bacteriostatic activity on Gram-positive organisms, whereas in association they exhibit a strong and synergistic bactericidal effect. The 13-OH function of PIIA is essential for antibiotic activity to occur whereas the 15-carbonyl function can be reduced with the retention of the biological properties of the drug. The carbonyl function of PIA can be reduced and the pipecolic moiety can be replaced by other groups without a dramatic influence on the antibiotic activity. The macrocyclic lactone ring is necessary for antibiotic activity.

Acetylation↗
PubMed1985

Autoradiography of tissue distribution of the IIA constituent of the pristinamycins.

The tissue distribution of a radioactive analogue of the IIA constituent of the pristinamycins was studied in female mice by autoradiography. Examination of slides and photographs discloses the presence of the antibiotic on the skin and in the bone marrow only a short time after injection. Elimination of the antibiotic is quick and is mainly through the digestive tract.

Animals↗
PubMed1985

[Water-soluble derivatives of factor IA of pristinamycins. Interaction with the bacterial ribosome].

The IA component of pristinamycins is a depsipeptide with a bacteriostatic effect on Gram positive bacteria. IA is made bactericidal by association with the IIA component of pristinamycins. Use of IA is limited because of its poor solubility in water. For this reason several water soluble IA derivatives have been synthesized. As for IA, these derivatives are fluorescent, a property used to study the binding of each compound to bacterial ribosomes of Escherichia coli (G-) and Staphylococcus aureus (G+). Two different techniques were used: direct study of fluorescence of the ribosome-antibiotic complex, and study of polarization of the fluorescence of the antibiotic bound to its receptor site. In addition to determination of binding parameters, these techniques can evaluate molecular synergy between pristinamycin IA (PIA) derivatives and pristinamycin IIA (PIIA) derivatives. MICs for the tested molecules correlate strongly with their binding parameters.

Chemical Phenomena↗
PubMed1984

Effect of P and A site substrates on the binding of a macrolide to ribosomes. Analysis of the puromycin-induced stimulation.

The puromycin-induced stimulation of [3H]dihydrorosaramicin binding is due to a twofold increase in affinity of the macrolide antibiotic, with no change in the number of binding sites. Conversely, the binding of [3H]puromycin (A site) is stimulated by rosaramicin. The synergistic effect observed between the two antibiotics can be explained by a conformational change with positive effect, which occurs at the level of their binding sites. Various effectors of [3H]dihydrorosaramicin binding have been tested. Adenosine and dimethyladenosine stimulate the binding; phenylalanine, uridine and gougerotin (A site) have no effect whereas AMP, ADP, ATP, GTP, puromycin 5'-phosphate and lincomycin (P site) are inhibitors. These results point to the importance of the purine moiety in the stimulatory effect and of the phosphate function in reversing this effect. It is concluded that rosaramicin binds to the ribosomal P site and that the synergism observed between rosaramicin and puromycin may be related to interactions between the A and P sites.

Adenosine Triphosphate↗
PubMed1984

Comparison of fortimicins with other aminoglycosides and effects on bacterial ribosome and protein synthesis.

Fortimicins are bicyclic aminoglycoside antibiotics that contain a fortamine moiety instead of the deoxystreptamine found in other aminoglysides. Fortimicin A had a bactericidal effect on Escherichia coli and Staphylococcus epidermidis and was found to inhibit protein synthesis in vivo. In vitro, fortimicin A inhibited polyuridylic acid-directed phenylalanine polymerization and induced misreading, as shown by leucine incorporation. In contrast, fortimicin B had no effect on either polymerization or misreading. In assays programmed with natural mRNA, only a weak polymerization inhibition effect was observed with fortimicin A, whereas a strong stimulation was seen in the presence of fortimicin B. Both fortimicins A and B inhibited dissociation of 70S ribosomes into their subunits and neither was able to displace [3H]dihydrostreptomycin, [3H]tobramycin, or [3H]gentamicin from their respective binding sites on the 70S particle.

Aminoglycosides↗
PubMed1984

Sensitivity to nikkomycin Z in Candida albicans: role of peptide permeases.

The uptake of tritiated nikkomycin Z, a potent inhibitor of chitin synthetase, is mediated by a peptide transport system in Candida albicans. Kinetic transport assays with radioactive di- and tripeptides and competition studies suggest that two distinct systems operate in this yeast. Nikkomycin Z was transported through one of these systems, common to di- and tripeptides. A peptide transport-deficient mutant was isolated on the basis of its resistance to nikkomycin Z. The mutant lost most of its capacity to take up dipeptides but simultaneously increased its ability to transport tripeptides. These results indicate that C. albicans handles peptides through multiple transport systems and adjusts their expression to environmental conditions.

Aminoglycosides↗
PubMed1984

Pristinamycin accumulation by Staphylococcus aureus.

Pristinamycins IA and IIA (PIA and PIIA) accumulation by Staphylococcus aureus has been studied with two hydrogenated analogs, (H2)PIA and (H2)PIIA. Rapid accumulation of both antibiotics at 37 degrees C is observed and internal concentrations can reach up to 58-fold the external concentration; this accumulation cannot be reduced by either metabolic inhibitors or tetracycline. The synergistic activity of pristinamycins IA and IIA is not observed at the bacterial accumulation level. We propose that pristinamycins enter into bacteria by a passive diffusion process and that the internal concentration is maintained by binding of the antibiotic to the bacterial ribosomes.

Anti-Bacterial Agents↗
PubMed1984

Synthesis of sisamine and of pseudodisaccharide analogues.

Lividamine and paromamine were converted into two key intermediate ethylenic aldehydes 10a and 10b. Reductive amination of the two aldehydes yielded the protected sisamine 11a and the three analogs 11b, 12a and 12b. These four derivatives were deprotected to yield the four pseudodisaccharides 1a, 1b, 2a and 2b which were less active in vitro than neamine against Escherichia coli ATCC 9637 and Staphylococcus aureus 209P.

Aminoglycosides↗
PubMed1984

Synthesis of pseudotrisaccharides related to ribostamycin.

The three protected sisamine derivatives 2i, 2j and 3, with a free 5-hydroxyl group, have been synthesized. Glycosylation at the 5 position with various pentofuranose derivatives yielded after deprotection of the 6a approximately i ribostamycin related aminoglycoside. These pseudotrisaccharides showed only low antibacterial activities with respect to the parent compounds.

Anti-Bacterial Agents↗