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Overview

ABSTRACT The Pseudomonas aeruginosa efflux pumps MexAB-OprM, MexCD-OprJ, and MexEF-OprN play an important role in susceptibility to fluoroquinolones in vitro. To determine if levofloxacin MICs arising from different levels of expression of efflux pumps result in a proportional reduction in the response to levofloxacin in vivo, isogenic strains of P. aeruginosa were tested with levofloxacin in two mouse models of infection (sepsis and neutropenic mouse thigh models). The levofloxacin 50% effective doses (ED 50 s) increased proportionally with the MICs for most strains. Similarly, the 24-h area under the concentration-time curve (AUC)/MIC ratio that resulted in 90% of the maximum bactericidal activity (90% Emax ) exceeded 75 for all strains except those with elevated MICs due to MexEF-OprN overexpression. In these strains, levofloxacin ED 50 s were 2- to 10-fold lower than the ED 50 /MIC ratios in the other strains and 90% Emax AUC/MIC ratios were 2- to 4-fold lower than those predicted from pharmacodynamic modeling of efficacy against other strains. These data show that while the MexEF-OprN efflux pump can provide P. aeruginosa resistance to levofloxacin in vitro, it appears to be less efficient in providing resistance to levofloxacin in animal models of infection.

01 Jun 2003·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

Prodrugs of Cephalosporin RWJ-333441 (MC-04,546) with Improved Aqueous Solubility

Q2 · MEDICINE

Article

Author: Calkins, Trevor ; Price, Mary E. ; Dudley, Michael N. ; Huie, Keith ; Chen, Sharon ; Hecker, Scott J. ; Glinka, Tomasz W.

ABSTRACT To improve the aqueous solubility of anti-methicillin-resistant Staphylococcus aureus cephalosporin RWJ-333441 for parenteral administration, acyl derivatives of the C-3 primary amino group were prepared and evaluated for solubility, cleavage in serum in vitro, and conversion to RWJ-333441 in vivo. Improved solubility at physiologic pH values and release of RWJ-333441 in vitro and in vivo were observed for several prodrugs, including the aspartate derivative RWJ-333442.

01 Feb 2003·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

RWJ-54428 (MC-02,479), a New Cephalosporin with High Affinity for Penicillin-Binding Proteins, Including PBP 2a, and Stability to Staphylococcal Beta-Lactamases

Q2 · MEDICINE

Article

Author: Nguyen, Tien ; Mathias, Kristina ; Park, Craig ; Hakem, Samia ; Chamberland, Suzanne ; Dudley, Michael N. ; Liu, Eric ; Dupree, Kelly ; Malouin, Francois ; Chan, Christin ; Hoang, Monica ; Blais, Johanne

ABSTRACT RWJ-54428 (MC-02,479) is a new cephalosporin active against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The potency of this new cephalosporin against MRSA is related to a high affinity for penicillin-binding protein 2a (PBP 2a), as assessed in a competition assay using biotinylated ampicillin as the reporter molecule. RWJ-54428 had high activity against MRSA strains COL and 67-0 (MIC of 1 μg/ml) and also showed affinity for PBP 2a, with a 50% inhibitory concentration (IC 50 ) of 0.7 μg/ml. RWJ-54428 also displayed excellent affinity for PBP 5 from Enterococcus hirae R40, with an IC 50 of 0.8 μg/ml and a MIC of 0.5 μg/ml. The affinity of RWJ-54428 for PBPs of β-lactam-susceptible S. aureus (MSSA), enterococci ( E. hirae ), and Streptococcus pneumoniae showed that the good affinity of RWJ-54428 for MRSA PBP 2a and E. hirae PBP 5 does not compromise its binding to susceptible PBPs. RWJ-54428 showed stability to hydrolysis by purified type A β-lactamase isolated from S. aureus PC1. In addition, RWJ-54428 displayed low MICs against strains of S. aureus bearing the four classes of staphylococcal β-lactamases, including β-lactamase hyperproducers. The frequency of isolation of resistant mutants to RWJ-54428 from MRSA strains was very low. In summary, RWJ-54428 has high affinity to multiple PBPs and is stable to β-lactamase, properties that may explain our inability to find resistance by standard methods. These data are consistent with its excellent activity against β-lactam-resistant gram-positive bacteria.

100 Deals associated with Essential Therapeutics, Inc.

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100 Translational Medicine associated with Essential Therapeutics, Inc.

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Pipeline

Pipeline Snapshot as of 25 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

MC-04124 ( Bacterial efflux pump )	Gram-Negative Bacterial Infections More	Discontinued
MC-207252 ( P-gp )	Staphylococcal Infections More	Discontinued
RWJ-333442	Gram-Positive Bacterial Infections More	Discontinued
PLR-9	Bacterial Infections More	Discontinued
MC-510126	Bacterial Infections More	Discontinued