LI Q, DOPPALAPUDI VR, CASTILLO R, BUENO A, LEE JY, STONE G, ZHANG Q, CHEN SF, HONG HP, LIN SF, LU YY, MACDONALD J, GEORGOPAPADAKOU NH; Interscience Conference on Antimicrobial Agents and Chemotherapy (43rd: 2003: Chicago, Ill.).
Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2003 Sep 14-17; 43: abstract no. F-2142.
NewBiotics, Inc., San Diego, CA.
BACKGROUND: Enzyme-Catalyzed Therapeutic Activation (ECTA) represents a core technology of NewBiotics in which drug resistance is transformed into therapeutic advantage. In this approach, substrates for the enzyme are designed to be converted into cytotoxic agent(s) by the pathogen. NB2001 and NB2030 are cephalosporin-triclosan conjugates designed to release triclosan in the presence of beta-lactamase (lamectacins). While both showed excellent in vitro activity against clinically important bacteria, including MRSA, their in vivo activity was curtailed by their high serum protein binding. Triclosan analogs with reduced protein binding were therefore designed and synthesized and conjugated to the cephem nucleus to form new lamectacins. METHODS: MICs were determined by the broth microdilution method in accordance with the NCCLS guidelines. Serum protein binding was determined by the MIC shift assay. RESULTS: Of the triclosan analogs synthesized, NB3179/D35004, NB3180/D35005, which had nitrogen replacing carbon at C6, and, for NB3180/D35005, lacking a chloro-substituent at C-4 phenoxy moiety of triclosan, had the highest antibacterial activity, inhibitory activity against the FabI target and reduced serum binding. The corresponding cephalosporin conjugates were then synthesized. While NB3352 and NB3353 had reduced serum protein binding, they also had reduced antibacterial activity. CONCLUSION: The position at C-6 and C-4 chloro-substituent phenoxy moiety of triclosan are important for binding to serum protein, but also for antibacterial activity and inhibition of the FabI target. Cephalosporin conjugates with these triclosan analogs have reduced activity relative to NB2001 and NB2030.
Publication Types:
Keywords:
- Anti-Bacterial Agents
- Cephalosporins
- In Vitro
- Microbial Sensitivity Tests
- NB 2030
- Protein Binding
- Staphylococcal Infections
- Staphylococcus aureus
- Tetrazoles
- Triclosan
- beta-Lactamases
Other ID:
UI: 102265744
From Meeting Abstracts