SEARCH · PubMed Health

Results for “Streptogramin B”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources

PubMed1995

A mechanism of resistance to partial macrolide and streptogramin B antibiotics in Staphylococcus aureus clinically isolated in Hungary.

A plasmid pEP2104 originated from Staphylococcus aureus was clinically isolated in Hungary during 1977. The plasmid mediates inducible resistance to PMS-antibiotics; partial macrolide [the 14-membered macrolides, erythromycin (EM) and oleandomycin and the 16-membered macrolides mycinamicin I (MCM I) and mycinamicin II (MCM II)and type B streptogramin (MKM-B) antibiotics. The sequence of 31 amino acid residues obtained by N-terminal analysis of the 63kDa protein (MsrSA) present in the membrane from 8325(pEP2104) cells whose PMS-resistance was induced by a concentration of 1.35 micrograms EM/ml [EM-induced 8325(pEP2104)], was identical to the corresponding sequence in a membrane protein MsrA related to promoting efflux of [14C]EM [Ross J.I., et al., Mol. Microbiol., 4, 1207 (1990)]. A constitutive PMS-resistant strain 8325(pMC38) was obtained from the 8325( pEP2104) strain in the presence of 1 microgram MCMI/ml. No inactivation of EM in EM-induced 8325(pEP2104) was observed. Moreover, poly (A)-directed polylysine synthesis by a cell-free system containing ribosomes from EM-induced 8325 (pEP2104) cells and S100 from Escherichia coli was inhibited by not only EM but spiramycin and MKM-B [Matsuoka M., et al., Biol. Pharm. Bull., 16, 1288 (1993)]. In addition, ribosomes from both EM-induced 8325 (pEP2104) and 8325(pMC38) strains showed about the same affinity as those from the host stain. NCTC8325. These results suggest, that like MsrA protein, active drug-efflux due to MsrSA protein may be responsible for PMS-resistance. How can the 8325 (pMC38) strain discriminate PMS-antibiotics from most of 16-membered macrolides and lincosamides? A possible explanation is discussed in terms of the pKa-value related to the physicochemical nature of the antibiotics.

Amino Acid Sequence↗

PubMed1989

Characterisation and molecular cloning of the novel macrolide-streptogramin B resistance determinant from Staphylococcus epidermidis.

A total of 110 staphylococcal isolates from human skin were found to express a novel type of erythromycin resistance. The bacteria were resistant to 14-membered ring macrolides (MIC 32-128 mg/l) but were sensitive to 16-membered ring macrolides and lincosamides. Resistance to type B streptogramins was inducible by erythromycin. A similar phenotype, designated MS resistance, was previously described in clinical isolates of coagulase-negative staphylococci from the USA. In the UK, MS resistance is widely distributed in coagulase-negative staphylococci but was not detected in 100 erythromycin resistant clinical isolates of Staphylococcus aureus. Tests for susceptibility to a further 16 antibiotics failed to reveal any other selectable marker associated with the MS phenotype. Plasmid pattern analysis of 48 MS isolates showed considerable variability between strains and no common locus for the resistance determinant. In one strain of S. epidermidis co-resistance to tetracycline, penicillin and erythromycin (MS) was associated with a 31.5 kb plasmid, pUL5050 which replicated and expressed all three resistances when transformed into S. aureus RN4220. The MS resistance determinant was localised to a 1.9 kb fragment which was cloned on to the high-copy-number vector, pSK265. A constitutive mutant of S. aureus RN4220 containing the 1.9 kb fragment remained sensitive to clindamycin. This observation, together with the concentration-dependent induction (optimum 5 mg/l of erythromycin) of virginiamycin S resistance suggests that the MS phenotype is not due to altered expression of MLS resistance determinants (erm genes) but probably occurs via a different mechanism.

Cloning, Molecular↗

PubMed1997

Antibiotic resistance in Streptomyces lividans: fluorescence assay for streptogramin B lyase.

A fluorescence assay for streptogramin B lyase, an enzyme that confers resistance to streptogramin B antibiotics, has been developed. The antibiotic substrates are fluorescent and the linear peptide products formed in the lyase-catalyzed reaction are relatively nonfluorescent. The assay has potential for assessing bacterial resistance to streptogramin B antibiotics and will be utilized to direct the purification of streptogramin B lyase from bacterial extracts.

Anti-Bacterial Agents↗

PubMed2001

Vgb from Staphylococcus aureus inactivates streptogramin B antibiotics by an elimination mechanism not hydrolysis.

The streptogramin antibiotics were identified almost 50 years ago but have only recently found clinical use as a consequence of the increase in multidrug-resistant bacteria. Despite the fact that these antibiotics have historically not found intense clinical use, resistance to streptogramins exists. Streptogramins consist of a mixture of two components: cyclic polyunsaturated macrolactones (group A) and cyclic hexadepsipeptides (group B). The latter are cyclized through an ester bond between the hydroxyl group of an N-terminal threonine and the C-terminal carboxyl. Resistance to the B streptogramins can occur through the production of enzymes such as Vgb from Staphylococcus aureus. This enzyme had been assumed to be a lactonase that inactivates the cyclic antibiotic by linearization through hydrolytic cleavage of the ester bond. We have expressed recombinant Vgb in quantity and, using a combination of mass spectrometry, NMR, and synthesis of model depsipeptides, show unequivocally that streptogramin B inactivation does not involve hydrolysis of the ester bond. Rather, the hexadepsipeptide is linearized through an elimination reaction across the ester bond generating an N-terminal dehydrobutyrine group. Therefore, Vgb is not a hydrolase but a lyase. We also have explored the activity of Vgb orthologues present in the chromosomes of various bacteria including Bordetella pertussis and Streptomyces coelicolor and have determined that these enzymes also show streptogramin B inactivation through an elimination mechanism indistinguishable to that used by Vgb. These results demonstrate that Vgb is a member of a large group of streptogramin B lyases that are present not only in resistant clinical isolates but also in the chromosomes of many bacteria. There is therefore a significant reservoir of streptogramin resistance enzymes in the environment, which has the potential to impact the long-term utility of these antibiotics. This research establishing the molecular mechanism of streptogramin resistance therefore has the potential to be exploited in the discovery of inhibitory compounds that could rescue antibiotic activity even in the presence of resistance elements.

Anti-Bacterial Agents↗

PubMed2004

Pneumococcal resistance to macrolides, lincosamides, ketolides, and streptogramin B agents: molecular mechanisms and resistance phenotypes.

The macrolides, lincosamides, ketolides, and streptogramin B agents (the MLKS(B) antimicrobial agents) have related chemical structures and share similar molecular targets on the 50S ribosomal subunit of Streptococcus pneumoniae. Mutations in rRNA or ribosomal proteins generate a variety of resistance phenotypes. The M phenotype of S. pneumoniae, which predominates in North America, affords low-level resistance to macrolides only (excluding macrolides with 16-member rings) by means of an efflux pump encoded by the mefA gene. The MLS(B) phenotype, which predominates in Europe, affords high-level resistance to macrolides, lincosamides, and streptogramin B agents and arises, in most cases, from dimethylation of adenine 2058 in the 23S rRNA of the 50S ribosomal subunit. Other, less common, phenotypes arise from other 23S rRNA modifications (ML and K phenotypes) or from amino acid substitution (MS(B) phenotype) or insertion (MKS(B) phenotype) into the 50S subunit ribosomal protein L4. In all cases, the decrease in susceptibility to ketolides (for example, telithromycin) is less than the decrease in susceptibility for other MLKS(B) agents.

Amino Acid Substitution↗

PubMed1998

Site-specific mutations in the 23S rRNA gene of Helicobacter pylori confer two types of resistance to macrolide-lincosamide-streptogramin B antibiotics.

Clarithromycin resistance in Helicobacter pylori is mainly due to A-to-G mutations within the peptidyltransferase region of the 23S rRNA. In the present study, cross-resistance to macrolide, lincosamide, and streptogramin B (MLS) antibiotics (MLS phenotypes) has been investigated for several clinical isolates of H. pylori. Two major types of MLS resistance were identified and correlated with specific point mutations in the 23S rRNA gene. The A2142G mutation was linked with high-level cross-resistance to all MLS antibiotics (type I), and the A2143G mutation gave rise to an intermediate level of resistance to clarithromycin and clindamycin but no resistance to streptogramin B (type II). In addition, streptogramin A and streptogramin B were demonstrated to have a synergistic effect on both MLS-sensitive and MLS-resistant H. pylori strains. To further understand the mechanism of MLS resistance in H. pylori, we performed in vitro site-directed mutagenesis (substitution of G, C, or T for A at either position 2142 or 2143 of the 23S rRNA gene). The site-directed point mutations were introduced into a clarithromycin-susceptible strain, H. pylori UA802, by natural transformation followed by characterization of their effects on MLS resistance in an isogenic background. Strains with A-to-G and A-to-C mutations at the same position within the 23S rRNA gene had similar levels of clarithromycin resistance, and this level of resistance was higher than that for strains with the A-to-T mutation. Mutations at position 2142 conferred a higher level of clarithromycin resistance than mutations at position 2143. All mutations at position 2142 conferred cross-resistance to all MLS antibiotics, which corresponds to the type I MLS phenotype, whereas mutations at position 2143 were associated with a type II MLS phenotype with no resistance to streptogramin B. To explain that A-to-G transitions were predominantly observed in clarithromycin-resistant clinical isolates, we propose a possible mechanism by which A-to-G mutations are preferentially produced in H. pylori.

Anti-Bacterial Agents↗

PubMed1985

Nucleotide sequence of ermA, a macrolide-lincosamide-streptogramin B determinant in Staphylococcus aureus.

The complete nucleotide sequence of ermA, the prototype macrolide-lincosamide-streptogramin B resistance gene from Staphylococcus aureus, has been determined. The sequence predicts a 243-amino-acid protein that is homologous to those specified by ermC, ermAM, and ermD, resistance determinants from Staphylococcus aureus, Streptococcus sanguis, and Bacillus licheniformis, respectively. The ermA transcript, identified by Northern analysis and S1 mapping, contains a 5' leader sequence of 211 bases which has the potential to encode two short peptides of 15 and 19 amino acids; the second, longer peptide has 13 amino acids in common with the putative regulatory leader peptide of ermC. The coding sequence for this peptide is deleted in several mutants in which macrolide-lincosamide-streptogramin B resistance is constitutively expressed. Potential secondary structures available to the leader sequence of the wild-type (inducible) transcript and to constitutive deletion, insertion, and point mutations provide additional support for the translational attenuation model for induction of macrolide-lincosamide-streptogramin B resistance.

Amino Acid Sequence↗

PubMed2000

[Study of macrolide, lincosamide, and streptogramin B antibiotics resistance in Staphylococcus aureus].

Macrolide antibiotics (Mac) consist of a 12- to 16-membered lactone ring combined with a sugar moiety, and they inhibit protein synthesis via binding to 23S ribosomal RNA in bacteria. The 14- and 16-membered Mac are used for treating infectious diseases caused by Gram-positive and other bacteria; e.g., Haemophilus influenzae, Bordetella pertussis, Legionella pneumophila, Campylobacter, Treponema pallidum and Mycoplasma. Resistance to macrolide, lincosamide, and streptogramin-B (MLS) antibiotics in staphylococci is known to have the following mechanisms: 1) alteration of the target on ribosome due to dimethylation of a specific adenine residue in the 23S ribosomal RNA by the product of the erm gene, and consequently a decrease in binding of MLS antibiotics; 2) inactivation of streptogramin-B (STG-B) and lincosamide by the products of the sbh (encoding streptogramin B hydrolase) and linA' (encoding 3-lincomycin 4-clindamycin O-nucleotidyltransferase) genes, respectively; and 3) active efflux of Mac and STG-B antibiotics determined by the msrA and msrB genes in Staphylococcus epidermidis and Staphylococcus xylosus, respectively, both of which appear to act as an ATP-dependent efflux pump. I have shown that Staphylococcus aureus 8325(pEP2104) exhibits inducible resistance to PMS (partial macrolide and streptogramin B)-antibiotics [the 14-membered macrolides, erythromycin (EM), and oleandomycin (OL), and the 16-membered macrolide mycinamicin (MCM) and STG-B]. The sequence of the N-terminal amino acid residues of a 63 kDa protein (MsrSA) that appeared in the membrane of PMS-resistant strains was identical to that of an MsrA polypeptide related to enhanced efflux of [14C]EM. Ribosomes from PMS-resistant strains showed a similar affinity for EM to those from the PMS-sensitive host strain NCTC8325, and no inactivation of EM by 8325(pEP2104) was observed. In the present study, I showed the DNA sequence of the msrSA region on the constitutive PMS-resistant plasmid pMC38, PMS-inducible resistant plasmid pEP2104 and PMS-sensitive mutant plasmid pSP6, and the region that is essential for inducible expression in PMS resistance. In addition, I investigated the relationship between PMS resistance and intracellular accumulation of EM.

ATP-Binding Cassette Transporters↗

PubMed2003

The mechanism of action of macrolides, lincosamides and streptogramin B reveals the nascent peptide exit path in the ribosome.

The macrolide-lincosamide-streptogramin B class (MLS) of antibiotics contains structurally different but functionally similar drugs, that all bind to the 50S ribosomal subunit. It has been suggested that these compounds block the path by which nascent peptides exit the ribosome. We have studied the mechanisms of action of four macrolides (erythromycin, josamycin, spiramycin and telithromycin), one lincosamide (clindamycin) and one streptogramin B (pristinamycin IA). All these MLS drugs cause dissociation of peptidyl-tRNA from the ribosome. Josamycin, spiramycin and clindamycin, that extend to the peptidyl transferase center, cause dissociation of peptidyl-tRNAs containing two, three or four amino acid residues. Erythromycin, which does not reach the peptidyl transferase center, induces dissociation of peptidyl-tRNAs containing six, seven or eight amino acid residues. Pristinamycin IA causes dissociation of peptidyl-tRNAs with six amino acid residues and telithromycin allows polymerisation of nine or ten amino acid residues before peptidyl-tRNA dissociates. Our data, in combination with previous structural information, suggest a common mode of action for all MLS antibiotics, which is modulated by the space available between the peptidyl transferase center and the drug.

Anti-Bacterial Agents↗

PubMed1999

UV-induced modifications in the peptidyl transferase loop of 23S rRNA dependent on binding of the streptogramin B antibiotic, pristinamycin IA.

The naturally occurring streptogramin B antibiotic, pristinamycin IA, which inhibits peptide elongation, can produce two modifications in 23S rRNA when bound to the Escherichia coli 70S ribosome and irradiated at 365 nm. Both drug-induced effects map to highly conserved nucleotides within the functionally important peptidyl transferase loop of 23S rRNA at positions m2A2503/psi2504 and G2061/A2062. The modification yields are influenced strongly, and differentially, by P-site-bound tRNA and strongly by some of the peptidyl transferase antibiotics tested, with chloramphenicol producing a shift in the latter modification to A2062/C2063. Pristinamycin IA can also produce a modification on binding to deproteinized, mature 23S rRNA, at position U2500/C2501. The same modification occurs on an approximately 37-nt fragment, encompassing positions approximately 2496-2532 of the peptidyl transferase loop that was excised from the mature rRNA using RNAse H. In contrast, no antibiotic-induced effects were observed on in vitro T7 transcripts of full-length 23S rRNA, domain V, or on a fragment extending from positions approximately 2496-2566, which indicates that one or more posttranscriptional modifications within the sequence Cm-C-U-C-G-m2A-psi-G2505 are important for pristinamycin IA binding and/or the antibiotic-dependent modification of 23S rRNA.

Anti-Bacterial Agents↗

PubMed2000

The macrolide-lincosamide-streptogramin B resistance determinant from Clostridium difficile 630 contains two erm(B) genes.

The ErmB macrolide-lincosamide-streptogramin B (MLS) resistance determinant from Clostridium difficile 630 contains two copies of an erm(B) gene, separated by a 1.34-kb direct repeat also found in an Erm(B) determinant from Clostridium perfringens. In addition, both erm(B) genes are flanked by variants of the direct repeat sequence. This genetic arrangement is novel for an ErmB MLS resistance determinant.

Anti-Bacterial Agents↗

PubMed2000

Specific inhibition of 50S ribosomal subunit formation in Staphylococcus aureus cells by 16-membered macrolide, lincosamide, and streptogramin B antibiotics.

The translational functions of the bacterial ribosome are the target for a large number of antimicrobial agents. The 14- and 16-membered macrolides, the lincosamides, and the streptogramin B type antibiotics are thought to share certain inhibitory properties, based on both biochemical and genetic studies. We have shown previously that the 14-membered macrolides, like erythromycin, have an equivalent inhibitory effect on translation and the formation of the 50S ribosomal subunit in growing bacterial cells. To extend this work, we have now tested the 16-membered macrolides spiramycin and tylosin, the lincosamides lincomycin and clindamycin, and 3 streptogramin B compounds pristinamycin I(A), virginiamycin S, and CP37277. Each of these was a specific inhibitor of 50S subunit formation, in addition to having an inhibitory effect on translation. By contrast, two streptogramin A compounds, virginiamycin M1 and CP36926, as well as chloramphenicol, were effective inhibitors of translation without showing a specific effect on the assembly of the large ribosomal subunit. A combination of an A and B type streptogramin (virginiamycin M1 and pristinamycin I(A)) demonstrated a synergistic inhibition of protein synthesis without exhibiting a specific inhibition of 50S subunit formation. These results extend our observations on 50S assembly inhibition to the entire class of MLS(B) antibiotics and reinforce other suggestions concerning their common ribosome-binding site and inhibitory functions.

Anti-Bacterial Agents↗

PubMed2002

Analysis of macrolide-lincosamide-streptogramin B (MLS(B)) resistance determinant in strains of Clostridium difficile.

The macrolide-lincosamide-streptogramin B (MLSB) resistance determinants have been detected among Clostridia in both C. perfringens and C. difficile strains. Previous studies have shown that MLSB-resistant C. difficile strains can be differentiated by specific hybridizing bands using an erm(B) probe. A recent study has demonstrated that C. difficile 630, a strain highly resistant to clindamycin and erythromycin (MIC > or = 256 ml/L), showing a hybridizing band at 9.7 kb, contains two copies of an erm(B) gene. It was also hypothesized that C. difficile 630 erm(B) determinant has arisen from a progenitor, represented by the C. perfringens CP592 determinant, which contains only one copy of an erm(B) gene that differs from C. difficile 630 erm(B) for seven nucleotide substitutions. To investigate the possibility that C. difficile strains with hybridizing fragments of different molecular size have an erm(B) determinant not identical to the one described in C. difficile 630, we performed a genetic analysis on the erm(B) determinant in 18 C. difficile strains, isolated from different sources. The results showed a heterogeneity in erm(B) determinant: C. difficile strains with hybridizing bands at 7.3 or 3.7 kb contained only one erm(B) copy, whereas strains with a band at 9.7 kb had two copies. The majority of the toxigenic strains examined was characterized by only one erm(B) copy with a sequence identical to the one found in C. difficile 630 and a lower resistance level for erythromycin (MICs ranging from 16 to 24 ml/L). Differently, some strains had an erm(B) gene identical to the one found in C. perfringens CP592. PCR ribotyping and clustering analysis indicate that the examined resistant strains, except one, belong to the same genetic lineage. These results seem to support the hypothesis of the evolution of the C. difficile 630 erm(B) determinant. The functional significance of one or two copies of erm(B) gene in C. difficile strains should be further investigated.

Anti-Bacterial Agents↗

PubMed1997

Streptogramin B biosynthesis in Streptomyces pristinaespiralis and Streptomyces virginiae: molecular characterization of the last structural peptide synthetase gene.

Streptomyces pristinaespiralis and S. virginiae both produce closely related hexadepsipeptide antibiotics of the streptogramin B family. Pristinamycins I and virginiamycins S differ only in the fifth incorporated precursor, di(mono)methylated amine and phenylalanine, respectively. By using degenerate oligonucleotide probes derived from internal sequences of the purified S. pristinaespiralis SnbD and SnbE proteins, the genes from two streptogramin B producers, S. pristinaespiralis and S. virginiae, encoding the peptide synthetase involved in the activation and incorporation of the last four precursors (proline, 4-dimethylparaaminophenylalanine [for pristinamycin I(A)] or phenylalanine [for virginiamycin S], pipecolic acid, and phenylglycine) were cloned. Analysis of the sequence revealed that SnbD and SnbE are encoded by a unique snbDE gene. SnbDE (4,849 amino acids [aa]) contains four amino acid activation domains, four condensation domains, an N-methylation domain, and a C-terminal thioesterase domain. Comparison of the sequences of 55 amino acid-activating modules from different origins confirmed that these sequences contain enough information for the performance of legitimate predictions of their substrate specificity. Partial sequencing (1,993 aa) of the SnbDE protein of S. virginiae allowed comparison of the proline and aromatic acid activation domains of the two species and the identification of coupled frameshift mutations.

Amino Acid Sequence↗

PubMed1985

Molecular genetics of resistance to macrolides, lincosamides and streptogramin B (MLS) in streptococci.

Resistance to macrolides-lincosamides-streptogramin B (MLS phenotype) appears in almost all streptococcal species isolated from man. Genes coding for MLS resistance are located on plasmids and one MLS resistance transposon has been described. MLS resistance genes have also been found in a large number of plasmid-free strains. Plasmids of 17 to 20 megadaltons (Mdal) that code either for MLS or for both MLS and chloramphenicol resistance are found in streptococci of groups A, B, C, D (Streptococcus faecalis) and G. These plasmids have broad host ranges (conjugative intraspecies, interspecies and intergeneric transfer), display similar restriction enzyme patterns and share a considerable degree of homology (78 to 95%). One smaller non-conjugative MLS resistance plasmid has been isolated from Str. sanguis (4.5 Mdal). In group D (Str. faecalis, Str. faecium) streptococci, MLS resistance genes are also found on plasmids that carry other antibiotic resistance (tetracycline, chloramphenicol, high-levels of streptomycin and kanamycin). These multi-resistance plasmids are either conjugative or non-conjugative and are of various sizes and molecular species and those that have been tested have narrow host-ranges. The MLS resistance genes of one multi-resistant plasmid, isolated from a strain of Str. faecalis, are located on a transposon of 3.3 Mdal, Tn917. Hybridization studies, with MLS determinants as probes, reveal homologies among various plasmid-borne MLS resistance sequences. Elements that are thought to be chromosome-borne mediate multiple antibiotic resistance (including MLS) in streptococci of groups A, B, C, D (Str. bovis), F, G, Str. pneumoniae, Str. mitis, Str. sanguis and Str. milleri. Strains harbouring such elements contain no detectable plasmid DNA. In some of the strains these elements are conjugative; their resistance markers transfer en bloc at low frequency and display narrow host ranges. Such elements, from Str. pyogenes and Str. agalactiae, were found to translocate onto various streptococcal haemolysin-bacteriocin plasmids.

Anti-Bacterial Agents↗

PubMed1992

Inducible resistance to a 16-membered macrolide, mycinamicin, in Staphylococcus aureus resistant to 14-membered macrolides and streptogramin B antibiotics.

Staphylococcus aureus 8325(pEP2104), a transductant derived from S. aureus PM2104 isolated clinically in Hungary (L. Janosi, and E. Ban, Acta Microbiol. Acad. Sci. Hung., 29: 187-200, 1982), exhibited an inducible resistance to the 14-membered macrolides [erythromycin (EM) and oleandomycin (OL)] and streptogramin B (MKM-B) antibiotics, but not to the 16-membered macrolides and lincosamides. This resistance was referred to as PMS-resistance phenotype (L. Jánosi, Y. Nakajima, and H. Hashimoto, Microbiol. Immunol., 34: 723-735, 1990). In addition to EM, OL, and MKM-B, however, the strain was recently and first observed to have inducible resistance to mycinamicin, a 16-membered ring macrolide. Thereby, we propose that the reference stated just above as PMS-resistance has to be extended to such 16-membered macrolides as mycinamicin. An optimum concentration of erythromycin or oleandomycin for induction of PMS-resistance was 1.35 mu g/ml in the strain 8325(pEP2104). The concentration was about 30 times as great as that (0.05 mu g/ml) required for induction of well-known co-resistance to macrolide-lincosamide-streptogramin B antibiotics in S. aureus ISP447.

Anti-Bacterial Agents↗

PubMed1989

New macrolides active against Streptococcus pyogenes with inducible or constitutive type of macrolide-lincosamide-streptogramin B resistance.

Macrolide-resistant bacteria can be classified as inducibly resistant or constitutively resistant. Inducibly resistant bacteria are resistant to 14-membered macrolides, such as erythromycin and clarithromycin (A-56268), but are susceptible to the 16-membered macrolides, such as tylosin and spiramycin, as well as to clindamycin. Constitutively resistant bacteria are resistant to macrolide-lincosamide-streptogramin B antibiotics. In this study, the MICs of several erythromycin and clarithromycin analogs against macrolide-susceptible and macrolide-resistant Streptococcus pyogenes strains were determined. Four 11,12-carbamate analogs of clarithromycin had lower MICs than erythromycin did against S. pyogenes with the inducible or constitutive type of macrolide-lincosamide-streptogramin B resistance. Five 11,12-carbonate analogs of erythromycin with modifications at the 4" position of cladinose had lower MICs than did erythromycin against S. pyogenes with the constitutive type of resistance, and one of these compounds, which had a naphthyl-glycyl substitution at the 4" position, had a lower MIC than erythromycin against both the inducibly resistant and constitutively resistant strains. Two analogs of erythromycin with a modification on the 4" position of cladinose had lower MICs than erythromycin did against the constitutively resistant organisms but not against the inducibly resistant organisms. Thus, 14-membered macrolides can be modified so as to confer a low MIC when tested in vitro.

Aminoglycosides↗

PubMed1981

Naturally occurring macrolide-lincosamide-streptogramin B resistance in Bacillus licheniformis.

Resistance to the macrolide-lincosamide-streptogramin B (MLS) group of antibiotics is widespread and of clinical importance. B. Weisblum and his coworkers have demonstrated that this resistance is associated with methylation of the 23S ribosomal ribonucleic acid of the large ribosomal subunit which results in a diminished affinity of this organelle for these antibiotics (Lai et al, J. Mol. Biol. 74:67-72, 1973). We report that 10 of 15 natural isolates of Bacillus licheniformis, a common soil organism, are resistant to the MLS antibiotics. The properties of this resistance (high level of tolerance for erythromycin, broad cross-resistance spectrum, and inducibility) suggest that resistance is conferred as described above. The resistance determinant from one of these strains was cloned onto a B. subtilis plasmid vector, and the resulting hybrid plasmid (pBD90) was used to prepare radioactive probe deoxyribonucleic acid for hybridization studies. All of the resistance B. licheniformis strains studied exhibited homology with the pBD90 insert. Plasmid pBD90 showed no homology to the following staphylococcal and streptococcal MLS-resistance plasmids: pE194, pE5, pAM77, pI258. Plasmids pE194 and pE5, on the other hand, carry homologous MLS genes but showed no detectable homology to one another in their replication genes. pBD90 specified a 35,000-dalton erythromycin-inducible protein, detectable in minicells, which therefore appears different from the 29,000-dalton inducible resistance protein specified by pE194. We conclude that there are at least three distinct MLS resistance determinants to be found among gram-positive bacteria.

Anti-Bacterial Agents↗