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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↗
PubMed1998

Streptogramins and their potential role in geriatric medicine.

Despite advances in antimicrobial chemotherapy over recent decades, morbidity and mortality secondary to infection continues to rise. In addition, the incidence of infection caused by resistant organisms has also increased. Concurrently, the elderly are living longer than prior generations, often with disabling chronic diseases. The more debilitated of the geriatric population are at greater risk for infection, and more likely to acquire or develop antimicrobial resistant organisms. Gram-positive organisms are a source of resistance and commonly cause infection in older patients. Whereas resistance is a concern in all patients, in the elderly this is magnified by limitations in treatment options because of differences in pharmacokinetics and tolerance as compared with younger counterparts. Pharmacokinetic differences include changes in drug distribution and may arise as a result of diminished end organ function. Age-related decreases in renal function often impact on commonly prescribed antimicrobials. In addition, the elderly are more susceptible to drug-drug interactions because polypharmacy is common in this patient population. Streptogramins may offer a useful alternative in the treatment of infections in the elderly due to their coverage of organisms commonly causing infections in this population and because of their favourable pharmacokinetic profiles. While published experience is limited, streptogramins are not appreciably eliminated by the kidney and, therefore, they are less subject to age-related changes in renal elimination. What is required is multi-dose pharmacokinetic analysis of streptogramins in geriatric populations and subset analysis of patient use data on file. The following will provide the reader with the most recently presented data on streptogramin use and their potential. While focusing on potential use in the elderly, we have cited data and issues which we believe will be relevant in the geriatric population.

Aged↗
PubMed2001

Design of a novel mammalian screening system for the detection of bioavailable, non-cytotoxic streptogramin antibiotics.

Screening and development of new antibiotic activities to counteract the increasing prevalence of multidrug-resistant (MDR) human pathogenic bacteria has once again become a priority in human chemotherapy. Here we describe a novel mammalian cell culture-based screening platform for the detection of streptogramin antibiotics. Quinupristin-dalfopristin (Synercid), a synthetically modified streptogramin, is presently the sole effective agent in the treatment of some MDR nosocomial infections. A Streptomyces coelicolor transcriptional regulator (Pip) has been adapted to modulate reporter gene expression (SEAP, secreted alkaline phosphatase) in Chinese hamster ovary cells (CHO) in response to streptogramin antibiotics. This CHO cell-based technology was more sensitive in detecting the production of the model streptogramin pristinamycin, from Streptomyces pristinaespiralis, than antibiogram tests using a variety of human pathogenic bacteria as indicator strains. The reporter system was able to detect pristinamycin compound produced by a single S. pristinaespiralis colony. The assay was rapid (17 hours) and could be carried out in a high-throughput 96-well plate assay format or a 24-well transwell set-up. This novel mammalian cell-based antibiotic screening concept enables detection of bioavailable and non-cytotoxic representatives of a particular class of antibiotics in a single assay and represents a promising alternative to traditional antibiogram-based screening programs.

Alkaline Phosphatase↗
PubMed2004

Solid-phase synthesis of dihydrovirginiamycin S1, a streptogramin B antibiotic.

We describe the first solid-phase synthesis of dihydrovirginiamycin S(1), a member of the streptogramin B family of antibiotics, which are nonribosomal-peptide natural products produced by Streptomyces. These compounds, along with the synergistic group A components, are "last line of defense" antimicrobial agents for the treatment of life-threatening infections such as vancomycin-resistant enterococci. The synthesis features an on-resin cyclization and is designed to allow production of streptogramin B analogues with diversification at positions 1', 1, 2, 3, 4, and 6. Several synthetic challenges known to hinder the synthesis of this class of compounds were solved, including sensitivity to acids and bases, and epimerization and rearrangements, through the judicious choice of deprotection conditions, coupling conditions, and synthetic strategy. This work should enable a better understanding of structure-activity relationships in the streptogramin B compounds, possible identification of analogues that bypass known resistance mechanisms, and perhaps the identification of analogues with novel biological activities.

Anti-Bacterial Agents↗
PubMed2003

Bidirectional expression units enable streptogramin-adjustable gene expression in mammalian cells.

Serious initiatives in gene therapy and tissue engineering require a sophisticated molecular toolbox combining DNA transfer technologies, human-compatible transcription control systems, as well as compact and robust expression configurations. We have designed several versatile bidirectional expression cassettes that enable coadjustable expression of two desired transgenes in response to clinically licensed antibiotics of the streptogramin class (pristinamycin, Pyostacin, Synercid). The bidirectional expression modules consist of a central operator (PIR) that is specific for the pristinamycin-dependent transactivator (PIT). Streptogramin-adjustable binding of PIT to PIR transactivates two divergently oriented promoters and initiates transcription of the desired transgenes. The bidirectional expression module can be equipped with different minimal promoters and configured for expression of (1) two functional effector genes, (2) one effector gene and a reporter gene, (3) PIT and an effector gene to form a highly compact one-vector expression arrangement. We have validated the streptogramin-adjustable bidirectional expression technology in different basic and autoregulated expression configurations in a variety of mammalian and human cell lines.

Alkaline Phosphatase↗
PubMed2004

Solvent affects the conformation of virginiamycin M1 (pristinamycin IIA, streptogramin A).

The streptogramins are antibiotics which act by binding two different components at separate nearby sites on the bacterial 50S ribosome, inhibiting protein synthesis. The first component, a macrolactone, is common to many of the streptogramin antibiotics and, thus, is referred to by many names including virginiamycin M1(VM1), pristinamycin IIA, ostreogrycin A and streptogramin A. X-Ray crystallographic studies of VM1 bound to ribosomes and to a deactivating enzyme show a different conformation to that of VM1 in chloroform solution. We now report the results of high resolution 2D NMR experiments that show that the conformation of VM1 in dimethyl sulfoxide and methanol differs from both that in chloroform solution and in the bound form. The 3D structure and the 1H NMR and 13C NMR chemical shifts of VM1 in dimethyl sulfoxide and methanol are described.

Models, Molecular↗
PubMed2003

Isolation of streptogramin-resistant Enterococcus faecium from human and non-human sources in a rural community.

OBJECTIVES: To detect quinupristin-dalfopristin and virginiamycin M1 resistance in Enterococcus faecium from human, food and environmental sources. MATERIALS AND METHODS: Enterococcal isolates derived from human faeces and urine, meat and seawater were screened for resistance to quinupristin-dalfopristin and virginiamycin M1 by an agar dilution method. Identification of all E. faecium strains and the presence of streptogramin acetyltransferase genes were confirmed using a PCR method. RESULTS: No high-level quinupristin-dalfopristin-resistant strains were isolated. Two isolates from faeces and five from seawater were confirmed to be high-level virginiamycin M1-resistant E. faecium (MIC 32 mg/L); none of these carried the vat(D) or vat(E) acetyltransferase genes that mediate high-level resistance to streptogramin A compounds. CONCLUSION: High-level quinupristin-dalfopristin-resistant strains of E. faecium are uncommon in Cornwall. However streptogramin A-resistant strains were detected from human and animal sources.

Animals↗
PubMed2004

Phenotypic and molecular characterization of macrolide and streptogramin resistance in Streptococcus mitis from neutropenic patients.

OBJECTIVES: To determine the prevalence of macrolide and streptogramin resistance in Streptococcus mitis isolates from neutropenic patients and to identify mechanisms of macrolide and streptogramin resistance in resistant isolates. METHODS: MICs of erythromycin, spiramycin, lincomycin and pristinamycin were determined for S. mitis isolates. Macrolide-resistance genes were characterized by PCR and ribosomal mutations by sequencing. RESULTS: A total of 169 S. mitis isolates were recovered from 66 patients at the Tunisian Bone Marrow Transplant Centre. Of these, 120 (70%) were non-susceptible to erythromycin and one was resistant to pristinamycin; 48.5% of isolates had an MLSB phenotype with cross-resistance between erythromycin, spiramycin and lincomycin, 4% had a dissociated MLSB phenotype with resistance to erythromycin and spiramycin but apparent susceptibility to lincomycin and 47.5% displayed the M phenotype. Resistance determinants were characterized in 33 isolates. Ten of 14 isolates with the cross MLSB resistance contained an ermB-like gene and four a combination of ermB- and mefA-like genes. Four of the five isolates with a dissociated MLSB phenotype contained ermB-like and one a combination of ermB- and mefA-like genes. All the 14 isolates with an M phenotype contained mefA-like genes. The pristinamycin-resistant strain had G105 and A108 substitutions in the conserved C terminus of the L22 ribosomal protein. CONCLUSIONS: The prevalence of macrolide resistance is high in S. mitis from neutropenic patients and is due to the spread of ermB- or mefA-like genes alone or combined. Resistance to streptogramins is rare and in this case associated with ribosomal mutation.

Amino Acid Sequence↗
PubMed2002

Tn5406, a new staphylococcal transposon conferring resistance to streptogramin a and related compounds including dalfopristin.

We characterized a new transposon, Tn5406 (5,467 bp), in a clinical isolate of Staphylococcus aureus (BM3327). It carries a variant of vgaA, which encodes a putative ABC protein conferring resistance to streptogramin A but not to mixtures of streptogramins A and B. It also carries three putative genes, the products of which exhibit significant similarities (61 to 73% amino acid identity) to the three transposases of the staphylococcal transposon Tn554. Like Tn554, Tn5406 failed to generate target repeats. In BM3327, the single copy of Tn5406 was inserted into the chromosomal att554 site, which is the preferential insertion site of Tn554. In three other independent S. aureus clinical isolates, Tn5406 was either present as a single plasmid copy (BM3318), as two chromosomal copies (BM3252), or both in the chromosome and on a plasmid (BM3385). The Tn5406-carrying plasmids also contain two other genes, vgaB and vatB. The insertion sites of Tn5406 in BM3252 were studied: one copy was in att554, and one copy was in the additional SCCmec element. Amplification experiments revealed circular forms of Tn5406, indicating that this transposon might be active. To our knowledge, a transposon conferring resistance to streptogramin A and related compounds has not been previously described.

Anti-Bacterial Agents↗
PubMed2003

[Macrolides, ketolides and streptogramins].

Macrolides, ketolides and streptogramins are three families of antibiotics with different chemical structures, sharing the same mechanism of action. All three bind to distinct bases of the peptidyl transferase center of ARNr 23S. Their antibacterial spectrum practically overlaps, but dissimilarities in affinity and/or number of binding sites determine differences in the intensity of their antibacterial effects (bacteriostatic or bactericidae) and in their activity against strains with acquired resistance mechanisms. These agents are active against the majority of gram-positive microorganisms and many intracellular microorganisms for growth. Over the last five years in our country, the percentage of macrolide-resistant pneumococci and S. pyogenes strains has increased substantially. Telithromycin (ketolide) and Synercid (streptogramin) have shown maintained activity against these strains. Macrolides, ketolides and streptogramins are metabolized in the liver through CYP 3A4 and they can partially block the activity of the enzyme, interfering with the metabolism of other drugs that use the same metabolic pathway. There is little elimination through the urine, with the exception of clarithromycin. High concentrations are reached in the cellular cytoplasm, but they do not diffuse to the CSF. These agents are included among class B drugs for use during pregnancy. Tolerance to macrolides and telithromycin is good and they have few associated adverse effects. The main clinical indication for these drugs is in empirical treatment of mild to moderate, community-acquired, upper and lower respiratory tract infections. Synercid is indicated in the treatment of infections due to methicillin-resistant staphylococci and glycopeptide-resistant enterococci.

Anti-Bacterial Agents↗
PubMed1997

Probing the substrate specificity of an enzyme catalyzing inactivation of streptogramin B antibiotics using LC-MS and LC-MS/MS.

LC-MS and LC-MS/MS analyses indicated that an enzyme responsible for inactivating the antibiotic etamycin is specific for streptogramins and acts on both type B-I and B-II streptogramin subgroups. No enzymatic activity was detected for other cyclodepsipeptides such as surfactins and viscosin. It was demonstrated using analogs of etamycin that the picolinyl moiety is essential to obtain enzyme-generated ring-opened compounds. Because the picolinyl moiety is also essential for the biological activity of streptogramins, it is proposed that this residue is a distinctive topographic feature in the binding of this group of antibiotics to enzyme active sites.

Chromatography, Liquid↗
PubMed1989

Streptogramins-inactivating activity in three producer streptomycetes.

The mechanism of self-resistance in three streptogramins-producing streptomycetes was analysed. The three organisms had ribosomes which were sensitive both to A- and B-components of the streptogramin complex. However, cell-free extracts of these producers showed streptogramins-inactivating activity which was independent on the addition of exogenous cofactors (S-adenosylmethionine, ATP or acetyl coenzyme A). The activity was retained by the extracts after dialysis and inactivated by boiling, indicating the presence of enzymatic activity. The inactivating activity was found throughout the growth cycle of the organisms indicating a constitutive nature.

Enzymes↗
PubMedDate not supplied

An update of pTRIDENT multicistronic expression vectors: pTRIDENTs containing novel streptogramin-responsive promoters.

We present an update on the pTRIDENT multicistronic mammalian expression vectors and their implications in various metabolic engineering and therapeutic applications. The pTRIDENT vector family has been expanded by construction of a new set of pTRIDENT-based vectors containing constitutive promoters of human origin (ubiquitin C and EF-1alpha promoters) and selectable markers (zeocin resistance) and expressing different reporter genes (secreted alkaline phosphatase (SEAP) and the secreted single-chain urokinase-type plasminogen activator (low-M(r) u-PA)). In addition, we have constructed pTRIDENT derivatives with novel streptogramin-repressible and streptogramin-inducible promoters for simultaneous and adjustable expression of three different transgenes. Streptogramin-inducible and tetracycline-repressible pTRIDENT derivatives were used to simultaneously control expression of three fluorescent proteins in mammalian cells: the enhanced cyan fluorescent protein (CFP), the recently isolated red fluorescent protein (RFP, also designated dsRed), and the enhanced yellow fluorescent protein (YFP). Owing to their modular structure, the pTRIDENT vector family represents a construction kit for the design of novel multicistronic expression constructs.

Genetic Vectors↗
PubMed2001

Streptogramin- and tetracycline-responsive dual regulated expression of p27(Kip1) sense and antisense enables positive and negative growth control of Chinese hamster ovary cells.

We constructed a dual regulated expression vector cassette (pDuoRex) whereby two heterologous genes can be independently regulated via streptogramin- and tetracycline-responsive promoters. Two different constructs containing growth-promoting and growth-inhibiting genes were stably transfected in recombinant Chinese hamster ovary (CHO) cells that express the streptogramin- and tetracycline-dependent transactivators in a dicistronic configuration. An optimally balanced heterologous growth control scenario was achieved by reciprocal expression of the growth-inhibiting human cyclin-dependent kinase inhibitor p27(Kip1) in sense (p27(Kip1)S) and antisense (p27(Kip1)AS) orientation. Exclusive expression of p27(Kip1)S resulted in complete G(1)-phase-specific growth arrest, while expression of only p27(Kip1)AS showed significantly increased proliferation compared to control cultures (both antibiotics present), presumably by decreasing host cell p27(Kip1) expression. In a second system, a derivative of pDuoRex encoding streptogramin-responsive expression of the growth-promoting SV40 small T antigen (sT) and tetracycline-regulated expression of p27(Kip1) was stably transfected into CHO cells. Expression of sT alone resulted in an increase in cell proliferation, but the expression of p27(Kip1) failed to provide the expected G(1)-specific growth arrest despite having demonstrated expression of the protein. This illustrates the difficulty in balancing the complex pathways underlying cell proliferation control through the expression of two functionally distinct genes involved in those pathways, and how a single-gene sense/antisense approach using pDuoRex can overcome this barrier to complete metabolic engineering control.

Animals↗
PubMed1981

Macrolide-lincosamide-streptogramin resistance patterns in Clostridium perfringens from animals.

Different patterns of resistance against commonly used macrolide, lincosamide, and streptogramin antibiotics were found in Clostridium perfringens of animal origin. The patterns were designated as (i) macrolide-lincosamide-streptogramin group B generalized resistance, (ii) macrolide-lincosamide generalized resistance, (iii) macrolide-lincosamide inducible resistance, and (iv) macrolide-lincosamide-streptogramin low-level generalized resistance. The strains of the fourth pattern were able to inactivate pristinamycin and virginiamycin. The macrolide-susceptible strains showed a bimodal distribution of lincomycin and clindamycin susceptibility levels. The susceptible strains were inhibited by 0.25 micrograms of lincomycin per ml and 0.03 micrograms of clindamycin per ml. The low-level resistant strains were inhibited at concentrations of 2 to 4 micrograms of lincomycin per ml and 0.5 to 2 micrograms of clindamycin per ml.

Animals↗
PubMed1993

Identification of the satA gene encoding a streptogramin A acetyltransferase in Enterococcus faecium BM4145.

Enterococcus faecium BM4145, a clinical isolate from urine, was resistant to streptogramin group A antibiotics by inactivation. The strain harbored a plasmid containing a gene, satA, responsible for this resistance; this gene was cloned and sequenced. It encoded SatA, a protein deduced to be 23,634 Da in mass and homologous with a new family of chloramphenicol acetyltransferases described in Agrobacterium tumefaciens, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. The similarity of SatA to other acetyltransferases, LacA (thiogalactoside acetyltransferase) and CysE (serine acetyltransferase) from E. coli, and to two putative acetyltransferases, NodL from Rhizobium leguminosarum and Urf1 from E. coli, was also observed in a region considered to be the enzyme's active site. Acetylation experiments indicated that acetyl coenzyme A was necessary for SatA activity and that a single acetylated derivative of pristinamycin IIA was produced. Other members of the streptogramin A group such as virginiamycin M and RP54476 were also substrates for the enzyme. We conclude that resistance to the streptogramin A group of antibiotics in E. faecium BM4145 is due to acetylation by an enzyme related to the novel chloramphenicol acetyltransferase family.

Acetylation↗
PubMed1998

Characterization of a staphylococcal plasmid related to pUB110 and carrying two novel genes, vatC and vgbB, encoding resistance to streptogramins A and B and similar antibiotics.

We isolated and sequenced a plasmid, named pIP1714 (4,978 bp), which specifies resistance to streptogramins A and B and the mixture of these compounds. pIP1714 was isolated from a Staphylococcus cohnii subsp. cohnii strain found in the environment of a hospital where pristinamycin was extensively used. Resistance to both compounds and related antibiotics is encoded by two novel, probably cotranscribed genes, (i) vatC, encoding a 212-amino-acid (aa) acetyltransferase that inactivates streptogramin A and that exhibits 58.2 to 69.8% aa identity with the Vat, VatB, and SatA proteins, and (ii) vgbB, encoding a 295-aa lactonase that inactivates streptogramin B and that shows 67% aa identity with the Vgb lactonase. pIP1714 includes a 2,985-bp fragment also found in two rolling-circle replication and mobilizable plasmids, pUB110 and pBC16, from gram-positive bacteria. In all three plasmids, the common fragment was delimited by two direct repeats of four nucleotides (GGGC) and included (i) putative genes closely related to repB, which encodes a replication protein, and to pre(mob), which encodes a protein required for conjugative mobilization and site-specific recombination, and (ii) sequences very similar to the double- and single-strand origins (dso, ssoU) and the recombination site, RSA. The antibiotic resistance genes repB and pre(mob) carried by each of these plasmids were found in the same transcriptional orientation.

Acetyltransferases↗
PubMed1999

Effects of genes encoding resistance to streptogramins A and B on the activity of quinupristin-dalfopristin against Enterococcus faecium.

Quinupristin-dalfopristin is a streptogramin combination active against multiply resistant Enterococcus faecium. Among 45 E. faecium isolated from patients in various French hospitals, only two strains were intermediate (MIC = 2 microgram/ml) and one, E. faecium HM1032, was resistant (MIC = 16 microgram/ml) to quinupristin-dalfopristin, according to British Society for Antimicrobial Chemotherapy and National Committee for Clinical Laboratory Standards approved breakpoints. The latter strain contained the vgb and satA genes responsible for hydrolysis or acetylation of quinupristin and dalfopristin, respectively, and an ermB gene (also previously referred to as ermAM) encoding a ribosomal methylase. The two intermediate strains had an LS(A) phenotype characterized by resistance to lincomycin (L), increased MICs (>/=8 microgram/ml) of dalfopristin (streptogramin A [S(A)]), and susceptibility to erythromycin and quinupristin. This phenotype was also detected in eight other strains susceptible to quinupristin-dalfopristin. No genes already known and conferring resistance to dalfopristin by acetylation or active efflux were detected in these LS(A) strains. Nineteen other strains resistant to erythromycin but susceptible to the quinupristin-dalfopristin combination displayed elevated MICs of quinupristin after induction (from 16 to >128 microgram/ml) and contained ermB genes. The effects of ermB, vgb, and satA genes on the activity of the streptogramin combination were tested by cloning these genes individually or in various combinations in recipient strains susceptible to quinupristin-dalfopristin, E. faecium HM1070 and Staphylococcus aureus RN4220. The presence of both the satA and vgb genes (regardless of the presence of an ermB gene) was necessary to confer full quinupristin-dalfopristin resistance to the host. The same genetic constructs were introduced into E. faecium BM4107 which displays a LS(A) phenotype. Addition of the satA or vgb gene to this LS(A) background conferred resistance to quinupristin-dalfopristin.

Acetyltransferases↗