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PubMed1995

Cloning and analysis of structural genes from Streptomyces pristinaespiralis encoding enzymes involved in the conversion of pristinamycin IIB to pristinamycin IIA (PIIA): PIIA synthase and NADH:riboflavin 5'-phosphate oxidoreductase.

In Streptomyces pristinaespiralis, two enzymes are necessary for conversion of pristinamycin IIB (PIIB) to pristinamycin IIA (PIIA), the major component of pristinamycin (D. Thibaut, N. Ratet, D. Bisch, D. Faucher, L. Debussche, and F. Blanche, J. Bacteriol. 177:5199-5205, 1995); these enzymes are PIIA synthase, a heterodimer composed of the SnaA and SnaB proteins, which catalyzes the oxidation of PIIB to PIIA, and the NADH:riboflavin 5'-phosphate oxidoreductase (hereafter called FMN reductase), the SnaC protein, which provides the reduced form of flavin mononucleotide for the reaction. By using oligonucleotide probes designed from limited peptide sequence information of the purified proteins, the corresponding genes were cloned from a genomic library of S. pristinaespiralis. SnaA and SnaB showed no significant similarity with proteins from databases, but SnaA and SnaB had similar protein domains. Disruption of the snaA gene in S. pristinaespiralis led to accumulation of PIIB. Complementation of a S. pristinaespiralis PIIA-PIIB+ mutant with the snaA and snaB genes, cloned in a low-copy-number plasmid, partially restored production of PIIA. The deduced amino acid sequence of the snaC gene showed no similarity to the sequences of other FMN reductases but was 39% identical with the product of the actVB gene of the actinorhodin cluster of Streptomyces coelicolor A(3)2, likely to be involved in the dimerization step of actinorhodin biosynthesis. Furthermore, an S. coelicolor A(3)2 mutant blocked in this step was successfully complemented by the snaC gene, restoring the production of actinorhodin.

Amino Acid Sequence↗
PubMed1995

Purification of the two-enzyme system catalyzing the oxidation of the D-proline residue of pristinamycin IIB during the last step of pristinamycin IIA biosynthesis.

High levels of conversion of 14C-labelled pristinamycin IIB (PIIB) to pristinamycin IIA (PIIA) were obtained in vivo in Streptomyces pristinaespiralis and in some other streptogramin A producers. This established that PIIB was an intermediate on the pathway to PIIA. In addition, in vitro studies with cell-free protein preparations demonstrated that the oxidation of PIIB to PIIA is a complex process requiring NADH, riboflavin 5'-phosphate (FMN), and molecular oxygen. Two enzymes were shown to be necessary to catalyze this reaction. Both were purified to homogeneity from S. pristinaespiralis by a coupled enzyme assay based on the formation of PIIA and by requiring addition of the complementing enzyme. One enzyme was purified about 3,000-fold by a procedure including a decisive affinity chromatography step on FMN-agarose. It was shown to be a NADH:FMN oxidoreductase (E.C. 1.6.8.1.) (hereafter called FMN reductase), providing reduced FMN (FMNH2) to the more abundant second enzyme. The latter was purified only 160-fold and was called PIIA synthase. Our data strongly suggest that this enzyme catalyzes a transient hydroxylation of PIIB by molecular oxygen immediately followed by a dehydration leading to PIIA. The native PIIA synthase consists of two different subunits with Mrs of around 50,000 and 35,000, as estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, while the FMN reductase seems to be a monomer with a Mr of around 28,000 and containing one molecule of tightly bound FMN. Stepwise Edman degradation of the entire polypeptides or some of their trypsin-digested fragments provided amino acid sequences for the two isolated proteins.

Amino Acid Sequence↗
PubMed1977

Plasmid-mediated pristinamycin resistance. PAC IIA: a new enzyme which modifies pristinamycin IIA.

A wild strain of Staphylococcus aureus which inactivates a wide variety of antibiotics has been found to inactivate pristinamycin IIA, an antistaphylococcal antibiotic. This phenomenon has been demonstrated to be plasmid mediated. The plasmid directs the biosynthesis of an acetyltransferase which is able to O-acetylate the drug. We propose to call the new enzyme PAC (IIA): Pristinamycin acetyltransferase.

Acetyltransferases↗
PubMed1988

Comparative in-vitro activity of erythromycin, vancomycin and pristinamycin.

We have studied the in-vitro activity of erythromycin, vancomycin and pristinamycin against 1,006 clinical isolates comprising streptococci, staphylococci, Neisseria gonorrhoeae, Haemophilus influenzae and anaerobes. In-vitro studies show pristinamycin to inhibit staphylococci and streptococci, including erythromycin highly-resistant organisms, at a concentration of less than or equal to 0.78 mg/l. Although pristinamycin's mean MIC for streptococci is higher than that of erythromycin, pristinamycin is bactericidal, whereas erythromycin is bacteristatic against Streptococcus agalactiae and oral streptococci. Enterococci were less uniformly susceptible to pristinamycin: 58 of the 94 Enterococcus faecalis tested were resistant (MIC greater than or equal to 3.12 mg/l). 14 of the 15 isolates of Enterococcus faecium were inhibited by less than or equal to 1.56 mg/l pristinamycin. Pristinamycin showed poor activity against Haemophilus influenzae (mode MIC 1.56 and MIC90 of 3.12 mg/l) but all except two of the 100 Neisseria gonorrhoeae tested were inhibited by less than or equal to 0.78 mg/l pristinamycin. Pristinamycin inhibited all nine Clostridium spp. at less than or equal to 0.39 mg/l and 38 of 40 strains of anaerobic gram-positive cocci at less than or equal to 0.78 mg/l. It was less effective against the Bacteroides fragilis group: (MIC90 3.12 mg/l). Pristinamycin had poor bactericidal activity against the anaerobes tested.

Bacteria↗
PubMed1993

[Evaluation of in vitro activity of pristinamycin against Haemophilus influenzae].

The activity of pristinamycin against H. influenzae was evaluated using various in vitro tests. Minimal inhibitory concentrations (MICs) were determined by an agar dilution method. The range of MICs was from 0.25 mg/l to 8 mg/l. MIC 50 was 2 mg/l; MIC 90 was 4 mg/l. The activity of component pristinamycin II (PII) is similar to that of pristinamycin and superior to that of component pristinamycin I (PI). Minimal bactericidal concentrations (MBCs) were equal to or two times higher than MICs. Killing curves showed a bactericidal activity obtained after 6 hours at MIC x 2 and MIC x 4 of pristinamycin. Component PII exhibited a bactericidal activity at MIC x 4. The post-antibiotic effect was high with pristinamycin: after two hours of contact with the antibiotic, PAEs were 2 hours with 1 mg/l, from 4 to 6.8 hours with 2 mg/l, and 6.7 hours with 4 mg/l. The PAEs with component PII were from 1 hour to 2 hours at concentrations of 1, 2, or 4 mg/l. Antibiotic resistance to various antibiotics did not influence the antibacterial activity of pristinamycin. At a breakpoint < or = 2 mg/l, more than 85% of the strains were sensitive to pristinamycin. The unimodal distribution of the strains showed the lack of acquired resistance to pristinamycin in these bacterial species.

Dose-Response Relationship, Drug↗
PubMed1989

In-vitro activity of pristinamycin and its components against gram-negative anaerobic bacilli and Gardnerella vaginalis.

The comparative in-vitro activities of pristinamycin, its components pristinamycins I and IIA, erythromycin, clindamycin and metronidazole were studied against 174 clinical isolates of Gram-negative anaerobic bacilli and 24 strains of Gardnerella vaginalis. Susceptibilities were determined with an agar-dilution method. Against Bacteroides and Fusobacterium, pristinamycin was slightly less active than both clindamycin and metronidazole and more active than erythromycin. Against G. vaginalis, the activity of pristinamycin was similar to that of clindamycin and slightly inferior to that of erythromycin. Both pristinamycins I and IIA alone were generally inactive against the strains tested. Additionally, MICs for the B. fragilis group determined by a broth microdilution technique were one to two log2 lower than MICs obtained by agar-dilution. The bactericidal activity of pristinamycin and clindamycin was moderate and varied according to the strains tested. The chequerboard broth microdilution test against 20 strains of the B. fragilis group confirmed the synergy between pristinamycins I and IIA at every PI/PIIA ratio. Along with the activity against Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma and both aerobic and anaerobic Gram-positive bacteria, our results suggest that pristinamycin could be an effective drug in the treatment of gynaecological infections.

Anti-Bacterial Agents↗
PubMed2004

Drug skin tests in cutaneous adverse drug reactions to pristinamycin: 29 cases with a study of cross-reactions between synergistins.

The present study was made to determine the value of drug skin tests in patients with cutaneous adverse drug reactions (CADRs) due to a synergistin (pristinamycin) and to determine the frequency of cross-reactions between synergistins. 29 patients were referred during the onset of the CADR due to pristinamycin: 18 with maculopapular rash, 9 erythrodermas, 1 angioedema and 1 Stevens-Johnson syndrome. They all had patch tests with pristinamycin and, in most cases, with other synergistins [virginiamycin and dalfopristin-quinupristin (DQ)], prick tests (10 cases) and intradermal tests (IDT) (5 cases). Skin tests with synergistins were positive in 27 cases, patch tests with pristinamycin in 20/29 cases (69%), prick tests with pristinamycin in 3/9 cases on immediate (1 case) or on delayed (2 cases) readings, and IDT with DQ in 4/5 cases. Cross-reactions between synergistins occurred in 9/22 with virginiamycin and in 7/8 cases with DQ. Skin tests with synergistins are useful in investigating CADR due to pristinamycin. Synergistins are composed of 2 chains (1 depsipeptide and 1 macrocyclic lactone) with many structural analogies between all synergistins. According to the chemical structures and our results, it seems advisable to avoid all synergistins in patients with CADR due to pristinamycin.

Adolescent↗
PubMed2002

Oral pristinamycin versus standard penicillin regimen to treat erysipelas in adults: randomised, non-inferiority, open trial.

OBJECTIVE: To assess the efficacy and safety of oral pristinamycin versus intravenous then oral penicillin to treat erysipelas in patients in hospital. DESIGN: Multicentre, parallel group, open labelled, randomised non-inferiority trial. SETTING: 22 French hospitals. PARTICIPANTS: 289 adults admitted to hospital with erysipelas. RESULTS: At follow up (day 25-45) the cure rate (primary efficacy end point) for the per protocol populations was 81% (83/102) for pristinamycin and 67% (68/102) for penicillin. The planned interim analysis (global one sided type I error 5%) showed that the one sided 97.06% confidence interval of the observed difference (pristinamycin-penicillin) between cure rates (3.3% to infinity ) exceeded the -10% non-inferiority threshold. For the intention to treat populations the cure rate at follow up was 65% (90/138) for pristinamycin and 53% (79/150) for penicillin, with the one sided 97.06% confidence interval of the observed difference between cure rates (1.7% to infinity ) exceeding the -10% non-inferiority threshold. That the lower limit of the confidence interval exceeded the -10% threshold and was also >0 supports the hypothesis that pristinamycin is significantly superior at the 5% level. More adverse events related to treatment, as assessed by the investigators, were reported in the pristinamycin group than in the penicillin group. Most adverse events involved the gastrointestinal tract (nausea, vomiting, and diarrhoea) but were minor and usually did not require discontinuation of treatment. CONCLUSION: Pristinamycin could be an alternative to the standard intravenous then oral penicillin regimen used to treat erysipelas in adults in hospital, with the advantages of oral first line therapy.

Administration, Oral↗
PubMed2001

Novel pristinamycin-responsive expression systems for plant cells.

Novel gene regulation systems were designed for plant cells responsive to the streptogramin antibiotic pristinamycin. The pristinamycin-repressible plant gene regulation concept (PIPpOFF) is based on a transcriptional activator (PIT) which consists of the Pip protein, the repressor of the pristinamycin resistance operon of Streptomyces coelicolor, fused to the VP16 transactivation domain of the Herpes simplex virus. PIT mediates pristinamycin-repressible activation of a synthetic plant promoter (P(pPIR)) in tobacco cells consisting of a nine Pip-binding site-containing artificial operator (PIR3) placed upstream of a TATA-box derived from the cauliflower mosaic virus 35S promoter (P(CaMV35S)). Pristinamycin interferes with induction by negatively regulating the DNA-binding capacity of the Pip moiety of PIT. A second, streptogramin-inducible plant gene regulation system (PIPpON) was constructed by combining Pip expression with a plant-specific pristinamycin-inducible promoter (P(pPIRON)). P(pPIRON) consists of a PIR3 module cloned downstream of the strong constitutive plant promoter P(CaMV35S). As in the native Streptomyces configuration, Pip binds to its cognate sequence within P(pPIRON) in the absence of regulating antibiotic and silences the chimeric plant promoter. Upon addition of pristinamycin, Pip is released from the PIR3 operator and full P(CaMV35S)-driven expression of desired plant genes is induced. The PIPpOFF and PIPpON systems performed well in Nicotiana tabacum suspension cultures and promise to provide an attractive extension of existing plant gene regulation technology for basic plant research or biopharmaceutical manufacturing using plant tissue culture.

Amino Acid Sequence↗
PubMed1995

Interaction of pristinamycin IA with P-glycoprotein in human intestinal epithelial cells.

Pristinamycin IA is a cyclo-peptidic macrolactone antibiotic belonging to the streptogramin family. In the present work, the interaction of pristinamycin IA with the multidrug transporter P-glycoprotein was investigated in the differentiated human intestinal epithelial cell line Caco-2. Pristinamycin IA specifically inhibited the efflux of the P-glycoprotein substrate [3H]vinblastine, thus increasing the cellular accumulation of the drug. Pristinamycin IA also reduced by 70% the basolateral to apical secretion of [3H]vinblastine across Caco-2 cell monolayers. The cellular accumulation of [14C]pristinamycin IA was very low and was increased by P-glycoprotein inhibitors (verapamil, chlorpromazine and reserpine). The basolateral to apical transport of [14C]pristinamycin IA was 100-fold higher than apical to basolateral passage. This polarized transport was inhibited by verapamil and by ATP depletion. The results suggest that pristinamycin IA is a substrate for the P-glycoprotein, a finding which may have important consequences for the pharmacokinetics of this drug.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Purification of peptide synthetases involved in pristinamycin I biosynthesis.

Several assays of pristinamycin I synthetases based on adenylate or thioester formation were developed. Purification to near homogeneity of these enzymatic activities from cell extracts of Streptomyces pristinaespiralis showed that three enzymes could activate all pristinamycin I precursors. SnbA, a 3-hydroxypicolinic acid: AMP ligase activating the first pristinamycin I residue, was purified 200-fold, using an ATP-pyrophosphate exchange assay. This enzyme was shown to be a monomer with an Mr of 67,000 as estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Then a multifunctional enzyme, consisting of two identical subunits (SnbC) with Mrs of 240,000 and able to bind covalently L-threonine as a thioester, was purified 100-fold. This protein also activated L-aminobutyric acid, which is further epimerized to generate the third residue of the pristinamycin I macrocycle. A third protein, consisting of two identical subunits (SnbD) with Mrs estimated to be between 250,000 and 350,000, was purified 200-fold. This large enzyme catalyzed thioesterification and subsequent N-methylation of 4-dimethylamino-L-phenylalanine, the fifth pristinamycin I residue. SnbD could also activate L-proline, the fourth pristinamycin I residue, and some preparations retained a low but significant activity for the last two pristinamycin I precursors. Finally, a single polypeptide chain (SnbE) with an Mr of 170,000, catalyzing L-phenylglycine-dependent ATP-pyrophosphate exchange, was purified 3,000-fold and characterized. Stepwise Edman degradation of the entire polypeptides or some of their internal fragments provided amino acid sequences for the four isolated proteins. The purified SnbE protein was further shown to be a proteolytic fragment of SnbD.

Amino Acid Sequence↗
PubMed1999

[In vitro activity of pristinamycin on respiratory bacteria].

TWO-PHASE ACTION: Pristinamycin is composed of two active substances A and B. Pristinamycin A (SA) first binds to the ribosome subunit 50s. Pristinamycin B (SB) then locks onto SA causing irreversible inhibition of bacterial protein production. WELL-ADAPTED ACTIVITY SPECTRUM: A member of the streptogramin family of antibiotics, pristinamycin is active against the main bacteria causing respiratory tract infections (pneumococci, S. aureus, H. influenzae) as well as against mycoplasma and anaerobic pathogens. ANTI-PNEUMOCOCCI ACTIVITY: Minimal inhibitory concentrations measured over the last 5 years have confirmed that the antibacterial activity of pristinamycin against pneumococci remains unchanged even for strains which develop resistance to other antibiotics, particularly to penicillin or erythromycin. OTHER BACTERIA: The activity of pristinamycin against H. influenzae is a constant finding (unimodal distribution of MIC). The persistent of pristinamycin activity against S. aureus strains, excepting a few SA- resistant strains and SA + SB- resistant strains, is remarkable. MIC studies have also demonstrated the constant susceptibility of Moraxella catarrhalis, non-groupable streptococci, anaerobic bacteria, and Legionella pneumophila.

Anti-Bacterial Agents↗
PubMed1999

Cluster organization of the genes of Streptomyces pristinaespiralis involved in pristinamycin biosynthesis and resistance elucidated by pulsed-field gel electrophoresis.

Streptomyces pristinaespiralis synthesizes pristinamycin, a member of the streptogramin antibiotic family which consists of a mixture of two types of chemically unrelated compounds named pristinamycins I and pristinamycins II. In order to estimate the size of the Strep. pristinaespiralis chromosome and to elucidate the organization of the pristinamycin biosynthetic and resistance genes already identified, it was decided to use the pulsed-field gel electrophoresis technique. Results indicate that the Strep. pristinaespiralis chromosome is linear and about 7580 kb, as previously shown for several other Streptomyces species. By hybridization, it could be shown that the biosynthetic and resistance genes for pristinamycins I and pristinamycins II, except for the multidrug resistance gene ptr, are interspersed and seem to be organized as a single large cluster, covering less than 200 kb corresponding to 2.6% of the total size of the chromosome. The consequences and significance of such a genetic organization are discussed.

Journal Article↗
PubMed2005

Successful oral pristinamycin therapy for osteoarticular infections due to methicillin-resistant Staphylococcus aureus (MRSA) and other Staphylococcus spp.

OBJECTIVES: Oral treatment regimens for multiresistant methicillin-resistant Staphylococcus aureus (MRSA) infections are limited. In Australia, rifampicin plus fusidic acid is the usual treatment regimen following glycopeptide therapy but many patients are intolerant of this; some isolates are resistant; new oxazolidinones are expensive for routine use. Pristinamycin is a possible alternative and we report our experience with this agent. METHODS: The Department of Microbiology and Infectious Diseases, South Western Area Pathology Service treats patients drawn from the South Western Sydney Area Health Service that houses approximately 800,000 people and contains approximately 2000 acute care public hospital beds. Patients prescribed pristinamycin between 1 September 2000 and 31 January 2000 were identified from hospital pharmacy records. A retrospective chart review was performed. Accepted clinical definitions of osteomyelitis and septic arthritis were used. RESULTS: Twenty-seven patients were identified with osteoarticular infections. Twenty-four cases involved Staphylococcus aureus (multiresistant MRSA in 21 cases); three involved Staphylococcus epidermidis sensu stricto; four cases involved multiple organisms. Nineteen cases received pristinamycin monotherapy; the others received various combinations (fusidic acid with five; other antibiotics with three). Therapy was generally well tolerated; no haematological or biochemical toxicity was detected. Seven patients had minor gastrointestinal disturbance; and one developed rash. Four patients required dose reduction. Only four patients ceased pristinamycin due to intolerance. Treatment outcome was evaluated in 23 cases; cure was effected in 16 cases, five were successfully suppressed and two failed. There were no deaths. CONCLUSIONS: Oral pristinamycin is well tolerated and an important additional agent to treat osteoarticular infections with multiresistant MRSA and other staphylococci.

Administration, Oral↗
PubMed2005

Correlation of agar dilution and VITEK2 system for detection of resistance to macrolides, lincosamides and pristinamycin among Staphylococcus aureus and Staphylococcus epidermidis: association with genotypes.

The performance of the VITEK2 system was evaluated against the agar dilution reference procedure for testing susceptibility of Staphylococcus aureus and Staphylococcus epidermidis to macrolides, lincosamides and streptogramins (MLS). Eighty clinical isolates were selected according to their resistance phenotype and genotype. Results for erythromycin and clindamycin showed 100% agreement; results for lincomycin showed agreement of 78%, with one very major error and 17 minor errors; and results for pristinamycin showed agreement of 46%, with one major error and 43 minor errors. Most isolates resistant to lincomycin and streptogramin A (L SgAr phenotype) were falsely susceptible to lincomycin, and intermediately-resistant or resistant to pristinamycin, with the VITEK2 system. No resistance gene was detected. Most (80%) isolates resistant constitutively to MLS (MLS(r)BC phenotype) were falsely intermediately-resistant to pristinamycin with the VITEK2 system. The erm(A) gene was more common than erm(C) in MLS(r)BC strains. Resistance to pristinamycin alone (SgA SgB PTr phenotype), or associated with either lincomycin resistance (L SgA SgB PTr phenotype) or constitutive MLS(B) resistance (MLS(BC) SgA PTr phenotype), was well-characterised without discordant results. Resistance to pristinamycin was always associated with resistance to streptogramin A, encoded by the vga(A), vga(B), vgb(A) and vat(A) genes in association with the erm(A) or erm(C) genes.

Agar↗
PubMed2005

Cloxacillin versus pristinamycin for superficial pyodermas: a randomized, open-label, non-inferiority study.

BACKGROUND: Superficial pyodermas may require systemic antibiotics. In a previous open-label trial, oxacillin and pristinamycin achieved similar cure rates, but its design was not truly that of a non-inferiority study. OBJECTIVES: To assess the efficacy and safety of oral cloxacillin versus pristinamycin (both 2 g/day) to treat superficial pyodermas. METHODS: Multicentre, parallel-group, open-label, randomized non-inferiority trial. RESULTS: French general practitioners in private practice included 334 out-patients (mean age: 42 years). At the follow-up (day 14), the cure rates (primary efficacy end point) for the intent-to-treat populations were 80.7% (138/171) for cloxacillin and 82.8% (135/163) for pristinamycin. The observed difference between cure rates was -2.1%, with the lower limit of the two-sided 95% confidence interval higher than the non-inferiority threshold of -15%. The per-protocol analysis yielded similar results. Therapy was discontinued for 10 patients (cloxacillin: 1, pristinamycin: 9; p = 0.01). CONCLUSION: Cloxacillin could be an alternative to pristinamycin in out-patients with superficial pyodermas.

Administration, Oral↗
PubMed1998

[In vitro activity of 10 antibiotics including pristinamycin and its two components (RP 12536 and 27404) against strict anaerobes].

The activities of the pristinamycin and its two components (RP 12536 and RP 27404) were investigated using the reference agar dilution method M11A3, on 175 anaerobic strains in comparison with that of erythromycin, clindamycin, metronidazole, amoxycillin either alone or combined with clavulanic acid, piperacillin, cefoxitin, cefotetan and cefotaxime. beta-lactamase production was detected for all the 55 B. fragilis group strains and 8/12 Prevotella and 2/18 Fusobacterium strains, respectively. On the whole anaerobes, resistance rates (%) were respectively: RP 27404 (69), RP 12536 (64), pristinamycin (5) erythromycin (31), clindamycin (17), metronidazole (7) amoxycillin (24), amoxycillin-clavulanic acid (2), piperacillin (7), cefoxitin (14), cefotetan (21) and cefotaxime (27). RP 27404 and 12536 had low activities on anaerobes but acted synergistically as pristinamycin. The greatest anti-anaerobic potencies were obtained with amoxycillin-clavulanic acid combination, pristinamycin, metronidazole and piperacillin. As resistance was not found for pristinamycin among Prevotella, Fusobacterium, Gram+ rods and Peptostreptococcus, this streptogramin may be an appropriate agent for the treatment of periodontitis, pulmonary, ENT, gynecologic and soft tissue infections where these anaerobes are frequently involved.

Anti-Bacterial Agents↗