Activities of a New Oral Streptogramin, XRP 2868, Compared to Those of Other Agents against
            <i>Streptococcus pneumoniae</i>
            and
            <i>Haemophilus</i>
            Species

Pankuch, Glenn A.; Kelly, Linda M.; Lin, Gengrong; Bryskier, A.; Couturier, Catherine; Jacobs, Michael; Appelbaum, Peter C.

doi:10.1128/aac.47.10.3270-3274.2003

Cited by 25 publications

(25 citation statements)

References 24 publications

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“…Possibly a more viable strategy for circumventing resistance mediated by Vgb is altering type B streptogramins so as to reduce the affinity to Vgb without affecting binding to the ribosome. There is a rich literature on the synthesis of type B streptogramin variants using diverse strategies including synthetic (24), semisynthetic (25), chemoenzymatic (23,26), and solid-phase synthesis approaches (27). The analysis presented here on the similarities and differences between the binding of quinupristin to Vgb vs. the natural target can guide which alterations may reduce the drugs' susceptibility to bacterial resistance.…”

Section: Discussionmentioning

confidence: 99%

Structural basis for streptogramin B resistance in Staphylococcus aureus by virginiamycin B lyase

Korczynska

Mukhtar

Wright

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The streptogramin combination therapy of quinupristin-dalfopristin (Synercid) is used to treat infections caused by bacterial pathogens, such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. However, the effectiveness of this therapy is being compromised because of an increased incidence of streptogramin resistance. One of the clinically observed mechanisms of resistance is enzymatic inactivation of the type B streptogramins, such as quinupristin, by a streptogramin B lyase, i.e., virginiamycin B lyase (Vgb). The enzyme catalyzes the linearization of the cyclic antibiotic via a cleavage that requires a divalent metal ion. Here, we present crystal structures of Vgb from S. aureus in its apoenzyme form and in complex with quinupristin and Mg 2؉ at 1.65-and 2.8-Å resolution, respectively. The fold of the enzyme is that of a seven-bladed ␤-propeller, although the sequence reveals no similarity to other known members of this structural family. Quinupristin binds to a large depression on the surface of the enzyme, where it predominantly forms van der Waals interactions. Validated by site-directed mutagenesis studies, a reaction mechanism is proposed in which the initial abstraction of a proton is facilitated by a Mg 2؉ -linked conjugated system. Analysis of the Vgb-quinupristin structure and comparison with the complex between quinupristin and its natural target, the 50S ribosomal subunit, reveals features that can be exploited for developing streptogramins that are impervious to Vgb-mediated resistance.antibiotic resistance ͉ enzyme mechanism ͉ crystal structure

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Section: Discussionmentioning

confidence: 99%

Structural basis for streptogramin B resistance in Staphylococcus aureus by virginiamycin B lyase

Korczynska

Mukhtar

Wright

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…XRP 2868 has been shown to exhibit broad and potent in vitro activity against gram-positive aerobic, fastidious gram-negative, and anerobic bacteria. Similar to other streptogramins, XRP 2868 has enhanced potency against grampositive cocci including multiple-drug-resistant Streptococcus pneumoniae (8,11). This novel compound is in early clinical development for the treatment of respiratory tract and skin infections.…”

mentioning

confidence: 99%

Pharmacodynamics of a New Streptogramin, XRP 2868, in Murine Thigh and Lung Infection Models

Andes

Craig

2006

Antimicrob Agents Chemother

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XRP 2868 is a new streptogramin antibiotic with broad-spectrum activity against gram-positive cocci. We used the neutropenic murine thigh and lung infection models to characterize the time course of antimicrobial activity of XRP 2868 and determine which pharmacokinetic/pharmacodynamic (PK/PD) parameter and magnitude best correlated with efficacy. Serum levels following four two-to fourfold-escalating single-dose levels of XRP 2868 were measured by liquid chromatography mass spectrometry assay. In vivo postantibiotic effects (PAEs) were determined after doses of 2.5, 10, and 40 mg/kg. Mice had 10 6.8 to 10 8.4 CFU/thigh of strains of Streptococcus pneumoniae ATCC 10813 or Staphylococcus aureus ATCC 29213 at the start of therapy when treated for 24 h with 2.5 to 640 mg/kg/day of XRP 2868 fractionated for 3-, 6-, 12-, and 24-h dosing regimens. Nonlinear regression analysis was used to determine which PK/PD parameter best correlated with CFU/thigh at 24 h. Streptogramins are naturally occurring antibiotics that act on the 50S ribosome. XRP 2868 is a new oral streptogramin that is comprised of a mixture of 70% RPR 132552A and 30% RPR 202868. XRP 2868 has been shown to exhibit broad and potent in vitro activity against gram-positive aerobic, fastidious gram-negative, and anerobic bacteria. Similar to other streptogramins, XRP 2868 has enhanced potency against grampositive cocci including multiple-drug-resistant Streptococcus pneumoniae (8,11). This novel compound is in early clinical development for the treatment of respiratory tract and skin infections.The goals of our experiments were to characterize the in vivo time course antimicrobial activity of XRP 2868 and determine the pharmacokinetic/pharmacodynamic (PK/PD) parameter and parameter magnitude predictive of efficacy. MATERIALS AND METHODSBacteria, media, and antibiotic. Nine strains of Streptococcus pneumoniae with variable resistance to penicillin (one penicillin-susceptible, four penicillin-intermediate, and four penicillin-resistant S. pneumoniae strains) were used. Six of the strains were also macrolide resistant. Four strains of Staphylococcus aureus (three methicillin-susceptible and one methicillin-resistant S. aureus strains) were also used for these experiments. Organisms were grown, subcultured, and quantified in Mueller-Hinton broth (Difco Laboratories, Detroit, MI) and Mueller-Hinton agar (Difco Laboratories, Detroit, MI) for all organisms except S. pneumoniae. Sheep blood agar plates (Remel, Milwaukee, WI) were utilized for S. pneumoniae. XRP 2868 was supplied by Aventis.In vitro susceptibility studies. The MICs of XRP 2868, penicillin, methicillin, and erythromycin for the various isolates were determined by standard Clinical Laboratory Standards Institute microdilution methods.Murine infection model. Animals were maintained in accordance with the American Association for Accreditation of Laboratory Animal Care criteria. All animal studies were approved by the Animal Research Committee of the William S. Middleton Memorial VA Hospital.Six-week-old,...

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“…The new compound was shown to inhibit staphylococci, Streptococcus pneumoniae, nonpneumococcal streptococci, Haemophilus influenzae, and anaerobes at concentrations of 1 g/ml or less (10,12,18). XRP2868 was approximately fourfold more potent than quinupristin-dalfopristin against Staphylococcus aureus and Enterococcus faecium (10).…”

mentioning

confidence: 99%

“…XPR2868 is a new investigational oral streptogramin that is composed of a mixture of 70% RPR132552 (streptogramin group A) and 30% RPR202868 (streptogramin group B) (18). The new compound was shown to inhibit staphylococci, Streptococcus pneumoniae, nonpneumococcal streptococci, Haemophilus influenzae, and anaerobes at concentrations of 1 g/ml or less (10,12,18).…”

mentioning

confidence: 99%

Activity of a New Oral Streptogramin, XRP2868, against Gram-Positive Cocci Harboring Various Mechanisms of Resistance to Streptogramins

Dupuis¹,

Leclercq²

2006

Antimicrob Agents Chemother

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The antibacterial activity of XRP2868, a new oral streptogramin composed of a combination of RPR132552 (streptogramin A) and RPR202868 (streptogramin B), was evaluated against a collection of clinical grampositive isolates with characterized phenotypes and genotypes of streptogramin resistance. The effects of genes for resistance to streptogramin A or B on the activity of XRP2868 and its components were also tested by cloning these genes individually or in various combinations in gram-positive recipient strains susceptible to quinupristin-dalfopristin. The species tested included Staphylococcus aureus, coagulase-negative staphylococci, Enterococcus faecalis, Enterococcus faecium, Streptococcus pneumoniae, and other species of streptococci. XRP2868 was generally fourfold more potent than quinupristin-dalfopristin against S. aureus, E. faecium, and streptococci and had activity against E. faecalis (MICs ‫؍‬ 0.25 to 1 g/ml). XRP2868 appeared to be affected by the same mechanisms of resistance as those to quinupristin-dalfopristin. Nevertheless, the strong activity of factor A of the oral streptogramin enabled the combination to be very potent against streptograminsusceptible staphylococci, streptococci, and E. faecium (MICs ‫؍‬ 0.03 to 0.25 g/ml) and to retain low MICs against the strains harboring a mechanism of resistance to factor A or factor B of the streptogramin. However, the combination of mechanisms of resistance to factors A and B caused an increase in the MICs of XRP2868, which reached 1 to 4 g/ml. As with the other streptogramins, there was a reduction in the bactericidal effect of XRPR2868 when the staphylococcal strains acquired a constitutively expressed erm gene.Multidrug resistance in gram-positive cocci has increased at an alarming rate in clinical settings worldwide, and overcoming bacterial resistance has become more important than ever. Several new drugs have been proposed as alternatives for the treatment of severe infections caused by multiply resistant gram-positive organisms, i.e., linezolid, daptomycin, tigecycline, and quinupristin-dalfopristin. Quinupristin-dalfopristin, an injectable streptogramin, was among the first to be developed internationally (3). Streptogramins have the advantage of bactericidal activity against pneumococci and staphylococci, provided that they are susceptible to clindamycin (11). However, quinupristin-dalfopristin can be administered only parenterally; and except for pristinamycin, which is available in France, oral streptogramins are not available (5). In addition, the administration of quinupristin-dalfopristin requires the presence of a deep-vein catheter because of venous toxicity (21). Therefore, the value of the international development of a new oral streptogramin that can be used as a replacement or as the treatment of first choice has become obvious.XPR2868 is a new investigational oral streptogramin that is composed of a mixture of 70% RPR132552 (streptogramin group A) and 30% RPR202868 (streptogramin group B) (18). The new compound was shown to inhibi...

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Activities of a New Oral Streptogramin, XRP 2868, Compared to Those of Other Agents against Streptococcus pneumoniae and Haemophilus Species

Cited by 25 publications

References 24 publications

Structural basis for streptogramin B resistance in Staphylococcus aureus by virginiamycin B lyase

Structural basis for streptogramin B resistance in Staphylococcus aureus by virginiamycin B lyase

Pharmacodynamics of a New Streptogramin, XRP 2868, in Murine Thigh and Lung Infection Models

Activity of a New Oral Streptogramin, XRP2868, against Gram-Positive Cocci Harboring Various Mechanisms of Resistance to Streptogramins

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