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PubMed1994

[A quantitative determination of inducibility by 14 membered ring macrolide antibiotics in inducible resistant Staphylococcus aureus to macrolide-lincosamide-streptogramin B antibiotics].

Using Staphylococcus aureus ISP447 strain, which shows inducible resistance to macrolide-lincosamide-streptogramin B (MLS) antibiotics, the extent of MLS-resistance induced by several macrolide antibiotics [erythromycin (EM), oleandomycin (OL), or roxithromycin (RXM)] was determined in terms of a relative ratio of a growth rate of the induced cells in the presence of a challenging drug, rokitamycin (RKM), to that of uninduced cells in the absence of RKM. The ratio was referred to as a relative inducibility (%). The inducibility was obtained at an optimum-induced condition by considering the following factors: (1) exponentially growing cells, (2) the optimum concentration of an inducer drug, i.e., 50, 150, and 150 ng/ml for EM, OL, and RXM, respectively, (3) a 3-h previous incubation at 37 degrees C in the presence of the inducer, and (4) 300 ng of RKM/ml, which is found to be optimum for induced cells to challenge, because of having no inducer activity. Using these qualification methods, inducibilities of EM, OL, and RXM as an inducer were 100.4, 27.9 and 81.1%, respectively. This method is allowed to be useful for the analysis of a structure-inducibility relationship.

Anti-Bacterial Agents↗
PubMed2000

Inversion of the anomeric configuration of the transferred sugar during inactivation of the macrolide antibiotic oleandomycin catalyzed by a macrolide glycosyltransferase.

Macrolides are a group of antibiotics structurally characterized by a macrocyclic lactone to which one or several deoxy-sugar moieties are attached. The sugar moieties are transferred to the different aglycones by glycosyltransferases (GTF). The OleI GTF of an oleandomycin producer, Streptomyces antibioticus, catalyzes the inactivation of this macrolide by glycosylation. The product of this reaction was isolated and its structure elucidated. The donor substrate of the reaction was UDP-alpha-D-glucose, but the reaction product showed a beta-glycosidic linkage. The inversion of the anomeric configuration of the transferred sugar and other data about the kinetics of the reaction and primary structure analysis of several GTFs are compatible with a reaction mechanism involving a single nucleophilic substitution at the sugar anomeric carbon in the catalytic center of the enzyme.

Amino Acid Sequence↗
PubMed1977

Macrolide resistance in Staphylococcus aureus: inducers of macrolide resistance.

Several macrolide-, lincosamide-, and streptogramin B-type (MLS) antibiotics were tested as inducers of erythromycin A (EM)-resistant [(14)C]leucine incorporation. Only 14-membered-ring macrolides having a glycosidically linked 6-deoxy sugar at the C-3 position of the lactone ring and the structurally dissimilar lincosamide, celesticetin, showed inducer activity. Modifications of EM at the C-4'' position of cladinose can apparently destroy the inducer property but do not affect the inhibitory properties of the antibiotic. The findings clearly show that inducer and inhibitor activities can be dissociated and are consistent with the concept that distinct binding/receptor sites are utilized for inhibition of ribosome function and induction of resistance.

Anti-Bacterial Agents↗
PubMed2001

Disruption of an Enterococcus faecium species-specific gene, a homologue of acquired macrolide resistance genes of staphylococci, is associated with an increase in macrolide susceptibility.

The complete sequence (1,479 nucleotides) of msrC, part of which was recently reported by others using a different strain, was determined. This gene was found in 233 of 233 isolates of Enterococcus faecium but in none of 265 other enterococci. Disruption of msrC was associated with a two- to eightfold decrease in MICs of erythromycin azithromycin, tylosin, and quinupristin, suggesting that it may explain in part the apparent greater intrinsic resistance to macrolides of isolates of E. faecium relative to many streptococci. This endogenous, species-specific gene of E. faecium is 53% identical to msr(A), suggesting that it may be a remote progenitor of the acquired macrolide resistance gene found in some isolates of staphylococci.

Amino Acid Sequence↗
PubMed1980

Field desorption mass spectrometry in structural studies of polyene macrolide antibiotics: isolation and early identification of a pentaene macrolide antibiotic.

Isolation of a pentaene macrolide antibiotic (NSC-277813) from Streptomyces griseus (FCRC-21) fermentation broth is described. Using field desorption mass spectrometry and high resolution field desorption mass spectrometry on the intact and derivatized antibiotic and degradation products, the antibiotic was identified as fungichromin. The application of field desorption mass spectrometry in the identification of polyene antibiotics is discussed.

Antibiotics, Antineoplastic↗
PubMed2003

In vitro activities of new ketolide, telithromycin, and eight other macrolide antibiotics against Streptococcus pneumoniae having mefA and ermB genes that mediate macrolide resistance.

The comparative in vitro activity of a new ketolide, telithromycin (TEL), and eight other macrolide-lincosamide antibiotics (MLS) against 215 strains, of Streptococcus pneumoniae including penicillin-resistant isolates (PRSP), was determined by the agar dilution method. These strains were isolated from patients with pneumonia, otitis media, and purulent meningitis between 1995 and 1997. Two genes, mefA and ermB, that encode MLS resistance in the strains were identified by polymerase chain reaction (PCR). Of the strains, 30.2% (n = 65) had the mefA gene, 37.7% (n = 81) had the ermB gene, and 1.4% (n = 3) had both resistant genes. The minimum inhibitory concentration (MIC90s) of TEL and 16-membered ring MLS for strains having the mefA gene were 0.063-0.25 microg/ml, which were the same level as those for MLS-susceptible strains. On the other hand, the strains with the mefA gene showed low-level resistance to 14- and 15-membered ring MLS, with MIC90s ranging from 1 to 4 microg/ml. Only the MIC90 of TEL at 0.5 microg/ml, for strains having the ermB gene was superior to that of the 14-, 15-, and 16-membered ring MLS (MIC90, > or =64 microg/ml). TEL also showed excellent activity against PRSP having abnormal pbp1a, pbp2x, and pbp2b genes. Most strains having the mefA and ermB genes were serotyped to 3, 6, 14, 19, and 23. These results suggest that TEL may be a useful chemotherapeutic agent for respiratory tract infections caused by S. pneumoniae.

Bacterial Proteins↗
PubMed2004

Isolation of cytotoxic chondropsins, macrolide lactams from the New-Caledonian marine sponge Psammoclemma sp. and electrospray ion trap multiple stage MS study of these macrolides.

Psammoclemma sp. (Phoriospongiidae) was selected for study through biological screening carried out in New Caledonia. The crude extract of Psammoclemma sp. was highly active on KB cells and its fractionation led to the isolation of two macrolides chondropsin A 1 and 73-deoxychondropsin A 2. The complex structures were elucidated by a combination of spectroscopic methods (NMR, ESI-MS/MS). These known compounds were evaluated for their cytotoxic activity towards several tumor cell lines and exhibited an IC50 of approximately 10(-10) M. Flow-cytometric analysis revealed that chondropsin A 1 and 73-deoxychondropsin A 2 blocked the entry of HL 60 and KB cells into G2/M phase, leading to cell death by apoptosis.

Animals↗
PubMed1989

Binding of novel macrolide structures to macrolides-lincosamides-streptogramin B-resistant ribosomes inhibits protein synthesis and bacterial growth.

Dimethylation of adenine 2058 in 23S rRNA renders bacteria resistant to macrolides, lincosamides, and streptogramin B (MLS resistance), because the antibiotic binding site on the altered 50S ribosomal subunit is no longer accessible. We now report that certain 6-O-methyl-11,12-cyclic carbamate derivatives of erythromycin are able to bind to dimethylated MLS-resistant 50S ribosomal subunits, thus inhibiting protein synthesis and cell growth. One of these novel structures, an 11-deoxy-11-(carboxyamino)-6-O-methylerythromycin A 11,12-(cyclic ester) derivative, structure 1a, was studied in detail. It inhibited in vitro protein synthesis in extracts prepared from both susceptible and MLS-resistant Bacillus subtilis with 50% inhibitory concentrations of 0.4 and 20 microM, respectively. The derivative bound specifically to a single site on the 50S subunit of MLS-resistant ribosomes prepared from B. subtilis and Staphylococcus aureus, and no binding to 30S subunits was observed. The association rate constant of derivative 1a with sensitive and resistant ribosomes was 100- and 500-fold slower, respectively, than that of the parent compound, erythromycin, with sensitive ribosomes. The dissociation rate constant of 1a from sensitive and resistant ribosomes was 50- to 100-fold slower than the rate of erythromycin dissociation from sensitive ribosomes. Furthermore, 1a binding to sensitive 50S subunits led to induction of ermC and ermD, while binding to resistant 50S subunits did not, showing that perturbation of sensitive and resistant 50S subunit function by 1a differs. These data demonstrated that 1a is unique in its interaction with MLS-resistant ribosomes and that this interaction causes a novel allosteric perturbation of ribosome function.

Anti-Bacterial Agents↗
PubMed1997

Cladinose analogues of sixteen-membered macrolide antibiotics. IV. Improved therapeutic effects of 4-O-acyl-L-cladinose analogues of sixteen-membered macrolide antibiotics.

Six derivatives of sixteen-membered macrolides possessing 4-O-acyl-alpha-L-cladinose as a neutral sugar were synthesized via 3"-methylthiomethyl ether intermediates in reasonable yield. Introduction of a methyl group on the 3"-hydroxyl group of midecamycin A1 was effective for enhancing its antibacterial activity. All these derivatives exhibited excellent therapeutic effects in mice, and some of them showed improved pharmacokinetics compared with the natural antibiotics (mycarose type) in mice. Facile synthesis of 9-O-acylated analogues are also described.

Animals↗
PubMed1998

Cladinose analogues of sixteen-membered macrolide antibiotics. VI. Synthesis of metabolically programmed, highly potent analogues of sixteen-membered macrolide antibiotics.

Five novel 3-hydroxyl derivatives of sixteen-membered macrolide possessing 4-O-acyl-alpha-L-cladinose as a neutral sugar moiety were synthesized by using a combination of structurally stable silyl acetal protection and selective hydrogenolysis of a 3"-methylthiomethyl ether to a 3"-OMe group. Several derivatives having n-butyryl, i-butyryl and n-valeryl substituent at the 4"-OH group exhibited significant antibacterial activity in vitro. One of them, 4"-O-n-butyryl-3"-O-methylleucomycin V, showed improved therapeutic effect in mice.

Animals↗
PubMed1977

Macrolide resistance in Staphylococcus aureus: induction of macrolide-resistant protein synthesis.

Induction of resistance to macrolide-, lincosamide-, and streptogramin B-type antibiotics in Staphylococcus aureus was studied by monitoring the appearance of erythromycin A (EM)-resistant [(14)C]leucine incorporation. Examination of the induction process revealed saturation kinetics and a time course much like that reported for penicillinase in gram-positive bacteria. Induction kinetics in exponentially growing cells were sigmoidal and appeared to reach a maximum and constant rate when growth reached stationary phase. Since the induction of EM-resistant colony-forming ability was complete within 60 min, ribosome modification cannot be limited to a fraction of the population and must occur in essentially every cell. However, EM-resistant growth was expressed in cells where less than half the [(14)C]leucine-incorporating activity was resistant to EM. This suggests that resistance requires that only a threshold level of ribosome modification be exceeded and that, once exceeded, resistance is dominant to sensitivity.

Anti-Bacterial Agents↗
PubMed1982

Synergistic effects of a macrolide and a cell wall-affecting antibiotic on Pseudomonas aeruginosa in vitro and in vivo. 1. Combined effects of a macrolide and a peptide antibiotic.

Synergistic effects of peptide and macrolide antibiotics against Pseudomonas aeruginosa were investigated in vitro and in vivo. Synergistic effects were evaluated by estimating the number of viable bacteria at varying intervals in the logarithmic growth phase. These bacteria were treated concurrently with polymyxin B (PL) at the final concentration of 1.56 U/ml and with 9,3"-di-O-acetylmidecamycin (MOM) at varying concentrations. Synergistic effect was observed when PL was used with MOM at 3.13 and 12.5 microgram/ml respectively. When MOM at 50 microgram/ml was used with PL, the viable bacterial count was reduced to below 1/300 of the control to which PL alone had been added. Thus, the synergistic effect was remarkable. Similar results were obtained when colistin methanesulfonate (CL) was used instead of PL. Subsequently, attempts were made to determine if this action could also be found in in vivo experiments using mice. PL or CL was injected intramuscularly and midecamycin (MDM) or MOM was administered once or repeatedly by the oral route. Simultaneously, Pseudomonas aeruginosa strain IFO 3455 was inoculated intraperitoneally to mice. In the case of treatment once or repeatedly using both PL and MDM or MOM, the survival rate of infected mice increased significantly compared to single treatment by PL alone. Thus, the synergistic effects were demonstrated in four experiments. (The significance levels for the experiments were P = 0.070, 0.015, 0.042 and 0.024). Similar results were obtained when strain No. 5 was used to infect mice (P = 0.0096, 0.0027). When CL and MOM were given to mice once prior to infection with strain No. 5, synergistic effects were obtained as well (P = 0.010, 0.034).

Animals↗
PubMed1982

Synergistic effects of a macrolide and a cell wall-affecting antibiotic on Pseudomonas aeruginosa in vitro and in vivo. 2. Combined effects of a macrolide with a fosfomycin and an aminoglycoside antibiotic.

Synergistic effects of the cell wall-affecting antibiotics, dibekacin (DKB) and fosfomycin (FOM) and a macrolide antibiotic, midecamycin (MDM) or its derivative 9,3"-di-O-acetylmidecamycin (MOM) against Pseudomonas aeruginosa were investigated in vitro and in vivo. Synergistic effects were evaluated by estimating the number of viable bacteria at varying intervals after the two kinds of antibiotics were added to the logarithmic phase of the bacterial solution. Six hours after addition of antibiotic, the viable bacterial count of the culture treated with FOM and MOM underwent 2 log reduction compared to that which treated with FOM alone. Thus synergistic effect was significant. The number of viable bacteria treated with DKB and MDM showed slight reduction at 3 hours after addition of the two antibiotics and a marked reduction was noted after 20 hours compared with the control. Synergistic action was also demonstrated in in vivo experiments using mice. Three experimental mouse infection models, intraperitoneal infection, subcutaneous infection with carrageenan solution and burn infection were used. FOM was administered subcutaneously. DKB was administered intramuscularly. MDM or MOM was administered by the oral route. In all three experiments the survival rate of infected mice treated with FOM and MOM increased significantly compared to control mice. Similar synergistic effect was also obtained with DKB and MDM.

Animals↗