Here are the two ICAAC abstracts related to KOSN that I found:
In Vitro and In Vivo Activities of 15-Methyl Ketolide Derivatives of Erythromycin A
D. R. ABBANAT1, G. ASHLEY2, J. CARNEY2, M. FARDIS2, B. FOLENO1, J. HILLIARD1, Y. LI2, P. LICARI2, M. LOELOFF1, M. MACIELAG1, J. MELTON1, S. STRYKER1, E. WIRA1, K. BUSH1; 1R.W. Johnson Pharmaceutical Research Institute, Raritan, NJ; 2Kosan Biosciences, Hayward, CA
Presentation Number: 1173
Keywords: ketolide, macrolide resistance, antibacterial
Background: Recent reports of improved activities of ketolides against resistant Gram-positive pathogens have caused a renewed interest in the discovery of novel macrolides. The ketolides RWJ-415663 and RWJ-415667 are 6-O-substituted derivatives prepared synthetically from 15-methylerythromycin A produced in a genetically engineered Streptomyces coelicolor strain. Methods: MICs were determined using NCCLS methods against a panel of 70 Gram-negative and Gram-positive strains. In vivo antibacterial efficacy was assessed in a murine Streptococcus pneumoniae lower respiratory tract infection model. The pharmacokinetics of single i.v., s.c. and p.o. doses were evaluated in mouse lung or plasma samples by bioassay. Results: MIC90 values for RWJ-415663 and RWJ-415667 were 0.12 mg/ml against each of the following groups of Gram-positive cocci: macrolide susceptible and resistant (mef, erm) streptococci, and macrolide susceptible and inducibly resistant (erm) staphylococci. In vivo ED50 values for RWJ-415663 and RWJ-415667 were 6 and 25 mg/kg, respectively (s.c.), and 6 and 4 mg/kg, respectively (p.o.). Pharmacokinetic analysis of orally dosed RWJ-415663 suggested that the plasma AUC/MIC ratio for Gram-positive cocci, a proposed measure of ketolide efficacy, was approximately 3.9-fold higher than that of telithromycin. Conclusions: (1) RWJ-415663 and RWJ-415667 had MIC90 values of 0.12 mg/mL against most macrolide-resistant Gram-positive pathogens. (2) In vivo ED50 values for RWJ-415663 and RWJ-415667 were comparable to or lower than those of telithromycin. (3) The pharmacodynamic parameters of these 15-methyl ketolides compared favorably to those for telithromycin.
Structure-Antibacterial Activity Relationships of Ketolides Derived from 15-Methylerythromycin A
M. MACIELAG1, D. ABBANAT1, G. ASHLEY2, E. BAUM1, M. FARDIS2, B. FOLENO1, H. FU2, E. GRANT1, T. HENNINGER1, J. HILLIARD1, D. HLASTA1, Y. LI2, J. MELTON1, E. WIRA1, K. BUSH1; 1R.W. Johnson Pharmaceutical Res. Inst., Raritan, NJ; 2Kosan Biosciences, Hayward, CA
Presentation Number: 1174
Keywords: ketolide, structure-activity, 15-methylerythromycin A
Background: Ketolides have promising activity against key respiratory pathogens, such as erythromycin-resistant Streptococcus pneumoniae. 15-Methylerythromycin A, obtained by chemobiosynthesis, was the starting material for the synthesis of two series of ketolides (Series I: R = heterocycloalkyl, R' = CH3, X = H or F; Series II: R = H, R' = heterocycloalkenyl, X = H or F). Methods: MICs were determined against selected Gram-negative and Gram-positive bacteria by NCCLS methods. In vivo efficacy was assessed in a murine septicemia model with Staphylococcus aureus Smith. Results: In both series, variation in the nature of the heterocyclic substituent led to analogs with MICs of <0.015 - 0.5 mcg/ml against streptococci containing erm and mef determinants. Fluorination of the C-2 position in series I improved the antibacterial profile, particularly against Haemophilus influenzae. Selected compounds were efficacious in the murine septicemia model (ED50s of 2.5 - 7.2 mg/kg s.c.). Conclusion: Optimization of the heterocyclic sidechain and the C-2 substituent affords 15-methyl ketolides with antibacterial profiles comparable to telithromycin.
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