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

Capmau, Marie-Louise; Bonnet, Didier; Cerceau, Claude; Soussy, C. J.; Dublanchet, A.; Duval, J

doi:10.7164/antibiotics.30.665

Cited by 52 publications

(37 citation statements)

References 3 publications

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“…There are several proposed mechanisms of resistance to macrolide, lincosamide, and streptogramin antibiotics, including target modification, antibiotic inactivation, and active efflux (21,22). On the basis of the changes in the MICs of erythromycin and RP 59500 and the lack of changes to the lincomycin MIC, the resistance of isolates from the fibrin clot model experiment may be due to either target modification or active efflux (21).…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamics of RP 59500 alone and in combination with vancomycin against Staphylococcus aureus in an in vitro-infected fibrin clot model

Kang

Rybak

1995

Antimicrob Agents Chemother

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The bactericidal activity and emergence of resistance to RP 59500 (quinupristin/dalfopristin) when it was administered alone and in combination with vancomycin against fibrin clots that have been infected with methicillin-susceptible Staphylococcus aureus ATCC 25923 or methicillin-resistant S. aureus (MRSA) 67 were evaluated in an in vitro pharmacodynamic infected fibrin clot model. Fibrin clots were infected with S. aureus to achieve an inoculum of approximately 10 9 CFU/g. Antibiotics were administered to simulate pharmacokinetics in humans: RP 59500 (7.5 mg/kg of body weight) every 8 h and vancomycin (15 mg/kg) every 12 h over 72 h. Preliminary test tube time-kill experiments with an inoculum of ϳ10 5 CFU/ml suggested that RP 59500 was more rapid in achieving a 99.9% reduction in the number of CFU per milliliter than vancomycin against ATCC 25923 (6.94 versus 24 h; P ‫؍‬ 0.0003) and MRSA 67 (6.77 versus 17.03 h; P ‫؍‬ 0.004). At a higher inoculum (ϳ10 8 CFU/ml), 99.9% kill was achieved only with the combination regimen against ATCC 25923 and MRSA 67 (10.9 and 10.5 h, respectively), with total reductions of 6.35 and 6.33 log 10 CFU/ml over 24 h, respectively. In the fibrin clot model, RP 59500 was more effective than vancomycin in reducing organism titers over 72 h. However, the combination regimen was the most effective therapy, with a total reduction of colony count against ATCC 25923 (total reduction of 1.24 log 10 CFU/g for RP 59500, 0.56 log 10 CFU/g for vancomycin, and 3.3 log 10 CFU/g for the combination; P < 0.002) and MRSA 67 (total reduction of 1.66 log 10 CFU/g for RP 59500, 0.50 log 10 CFU/g for vancomycin, and 2.48 log 10 CFU/g for the combination; P < 0.04). Resistance of both strains of S. aureus was noted in the model only after exposure to RP 59500 (32-fold increase in the MIC), as was a simultaneous increase in the erythromycin MIC (32-fold) for ATCC 25923, but no changes in the lincomycin MIC were noted. Overall, RP 59500 demonstrated more potent bactericidal activity than vancomycin against S. aureus over 72 h. In the fibrin clot model, the most optimal therapy was the combination regimen.

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Section: Discussionmentioning

confidence: 99%

Pharmacodynamics of RP 59500 alone and in combination with vancomycin against Staphylococcus aureus in an in vitro-infected fibrin clot model

Kang

Rybak

1995

Antimicrob Agents Chemother

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“…An acetyltransferase that inactivates the A compounds was detected in the lysates of two pristinamycin-resistant staphylococcal isolates (10,22). The gene encoding this enzyme, vat, was recently isolated from a staphylococcal plasmid and sequenced (3).…”

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confidence: 99%

Analysis of pristinamycin-resistant Staphylococcus epidermidis isolates responsible for an outbreak in a Parisian hospital

Loncle

Casetta

Buu-Hoï

et al. 1993

Antimicrob Agents Chemother

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In 1990, over a 6-month period, an increase from 1 to 10%Y in the incidence of pristinamycin resistance among coagulase-negative staphylococci was observed in four intensive care units of a Parisian hospital.Twenty-three such isolates, as well as 25 pristinamycin-susceptible Staphylococcus epidermidis isolates, were collected and typed by analyzing various bacterial constituents. Two structurally related plasmids of 7.3 and 14.3 kb, carrying the gene vga encoding resistance to pristinamycin, were detected in the 23 pristinamycinresistant coagulase-negative staphylococci which were identified as S. epidermidis. Although related by numerous common characteristics, 20 of these 23 isolates could be divided into two types, A (17 isolates) and B (three isolates). These types were characterized on the basis of their plasmid contents and hybridization patterns obtained when the EcoRI-digested DNA was probed with plasmid pIP1551 containing an internal fragment of the insertion sequence IS256. These findings suggest that the dissemination of type A epidemic strains was, in large part, responsible for the outbreaL

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“…Vgb was first described in a clinical isolate of Staphylococcus aureus in 1977 (12). It has since been identified on a number of resistance plasmids in various Gram-positive bacterial pathogens.…”

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

Cited by 52 publications

References 3 publications

Pharmacodynamics of RP 59500 alone and in combination with vancomycin against Staphylococcus aureus in an in vitro-infected fibrin clot model

Pharmacodynamics of RP 59500 alone and in combination with vancomycin against Staphylococcus aureus in an in vitro-infected fibrin clot model

Analysis of pristinamycin-resistant Staphylococcus epidermidis isolates responsible for an outbreak in a Parisian hospital

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

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