Delving into the Latest Updates on Flopristin/Linopristin with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Linopristin/flopristin

+ [3]

Target

50S subunit

Action

inhibitors

Mechanism

50S subunit inhibitors(50S ribosomal subunit inhibitors)

Therapeutic Areas

Infectious DiseasesRespiratory DiseasesSkin and Musculoskeletal Diseases

Active Indication-

Inactive Indication

Community Acquired PneumoniaPneumoniaSkin and skin structure infections

Originator Organization

Sanofi

Active Organization-

Inactive Organization

Novexel SA

Sanofi

License Organization-

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC78H101FN12O16

InChIKeyXWDVNPKQLGIFMX-BPNBPZSGSA-N

CAS Registry642080-29-3

Sequence Code 524728955

ABSTRACT Streptogramin antibiotics are divided into types A and B, which in combination can act synergistically. We compared the molecular interactions of the streptogramin combinations Synercid (type A, dalfopristin; type B, quinupristin) and NXL 103 (type A, flopristin; type B, linopristin) with the Escherichia coli 70S ribosome by X-ray crystallography. We further analyzed the activity of the streptogramin components individually and in combination. The streptogramin A and B components in Synercid and NXL 103 exhibit synergistic antimicrobial activity against certain pathogenic bacteria. However, in transcription-coupled translation assays, only combinations that include dalfopristin, the streptogramin A component of Synercid, show synergy. Notably, the diethylaminoethylsulfonyl group in dalfopristin reduces its activity but is the basis for synergy in transcription-coupled translation assays before its rapid hydrolysis from the depsipeptide core. Replacement of the diethylaminoethylsulfonyl group in dalfopristin by a nonhydrolyzable group may therefore be beneficial for synergy. The absence of general streptogramin synergy in transcription-coupled translation assays suggests that the synergistic antimicrobial activity of streptogramins can occur independently of the effects of streptogramin on translation.

01 Oct 2011·International Journal of Antimicrobial AgentsQ2 · MEDICINE

In vitro pharmacokinetic/pharmacodynamic activity of NXL103 versus clindamycin and linezolid against clinical Staphylococcus aureus and Streptococcus pyogenes isolates

Q2 · MEDICINE

Article

Author: Celine Vidaillac ; Jorge Parra-Ruiz ; Patricia Winterfield ; Michael J. Rybak

NXL103 (linopristin/flopristin, 30/70) is a novel oral streptogramin combination with activity against a large variety of multidrug-resistant Gram-positive pathogens. The objective of this study was to evaluate the in vitro activity of NXL103 in comparison with oral comparators (clindamycin and linezolid). Six clinical isolates [four meticillin-resistant Staphylococcus aureus (MRSA) and two Streptococcus pyogenes] were exposed for 48 h in an in vitro pharmacokinetic/pharmacodynamic (PK/PD) model at a starting inoculum of ca. 10(6) colony-forming units (CFU)/mL. Antimicrobial simulations included NXL103 500 mg every 12 h, linezolid 600 mg every 12 h and clindamycin 450 mg every 6 h. Bactericidal and static effects were defined as ≥3log(10) and <3log(10) CFU/mL kill from the starting inoculum, respectively. Experiments were performed in duplicate to ensure reproducibility, and differences between regimens were evaluated by analysis of variance (ANOVA) with Tukey's post-hoc test. NXL103 exhibited lower minimum inhibitory concentrations than comparators, with values ≤0.06 mg/L for S. pyogenes and 0.125-0.25 mg/L for MRSA isolates. In the PK/PD model, NXL103 demonstrated significantly better activity than linezolid and clindamycin (P<0.05), achieving sustained bactericidal activity within <2 h against S. pyogenes strains and between 7.3-32 h against MRSA isolates. In contrast, linezolid only exhibited a static effect, whereas clindamycin achieved 3log(10) kill at 6h against the unique clindamycin-susceptible S. pyogenes strain evaluated. In conclusion, at therapeutic concentrations NXL103 exhibits promising activity against both MRSA and S. pyogenes strains, including clindamycin-resistant organisms. Further in vitro and in vivo experiments are warranted to explore the therapeutic benefit of NXL103 for the treatment of Gram-positive skin and soft-tissue infections.

01 Apr 2011·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

Time-Kill Activity of the Streptogramin NXL 103 against Gram-Positive and -Negative Bacteria

Q2 · MEDICINE

Article

Author: Clark, Catherine ; Appelbaum, Peter C. ; Lin, Gengrong ; Pankuch, Glenn A.

ABSTRACTAgainst 33 Gram-positive and -negative bacteria, NXL 103 MICs were 0.03 to 1 μg/ml. NXL 103 was bactericidal by 12 h at 2 × MIC against all 5 pneumococci and at 2 × MIC after 24 h against all 5 group A and B β-hemolytic streptococci. NXL 103 was bactericidal against all 8Haemophilus influenzaestrains at 2× MIC and all 5Moraxella catarrhalisstrains at 4× MIC after 24 h but was mainly bacteriostatic against 5 methicillin-resistantStaphylococcus aureusstrains. After the exposure of one strain of each species to NXL 103 for 10 daily subcultures, the MICs remained within ±1 dilution.

100 Deals associated with Flopristin/Linopristin

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Community Acquired Pneumonia	Phase 2	Peru	Novexel SA	01 Oct 2007
Community Acquired Pneumonia	Phase 2	Croatia	Novexel SA	01 Oct 2007
Community Acquired Pneumonia	Phase 2	Poland	Novexel SA	01 Oct 2007
Community Acquired Pneumonia	Phase 2	Estonia	Novexel SA	01 Oct 2007
Community Acquired Pneumonia	Phase 2	Ukraine	Novexel SA	01 Oct 2007
Community Acquired Pneumonia	Phase 2	Romania	Novexel SA	01 Oct 2007
Community Acquired Pneumonia	Phase 2	Germany	Novexel SA	01 Oct 2007
Community Acquired Pneumonia	Phase 2	South Africa	Novexel SA	01 Oct 2007
Community Acquired Pneumonia	Phase 2	Chile	Novexel SA	01 Oct 2007
Pneumonia	Phase 2	-	Sanofi	-