The overall objective of this investigation is to understand how macrolide antibiotics like erythromycin inhibit the process of bacterial cell growth. This investigation will explore the new observation that erythromycin and other macrolide compounds can inhibit the assembly of the large ribosomal subunit in bacterial cells. Ribosome assembly will be analyzed in Staphylococcus aureus and Escherichia coli cells to define the inhibitory features of these compounds. The stage in the process at which assembly is affected and the ribosomal macromolecules involved will be identified. Macrolide compounds with structures related to erythromycin will be tested for their effects on assembly. Other antibiotics will be tested for both synergistic effects on the macrolide activity and for independent influences on ribosome assembly in sensitive cells. Ribosomal subunits will be reconstituted from component RNAs and proteins to define the molecules involved as targets for assembly inhibition. An investigation of this assembly-sensitive site and the mode of inhibition of assembly will reveal how macrolides are can have two inhibitory activities. The findings from this work will help in assessing the effectiveness of existing antibiotics and in developing new compounds as antimicrobial agents. The recent resurgence of antibiotic-resistant organisms underscores the importance of a better understanding of drug mechanisms, resistance modes and structural features necessary for optimal effectiveness.
| Champney, W S; Tober, C L (2001) Structure-activity relationships for six ketolide antibiotics. Curr Microbiol 42:203-10 |
