P4: Biosynthetic and structure-activity investigations on translation-inhibiting cyclic peptide natural products

This project deals with the potent translation inhibitor GE82832, that was shown to bind to protein S12 at the 30S unit of the bacterial ribosome, thereby preventing elongation factor Gcatalyzed tRNA translocation. GE82832 and its equipotent analogue dityromycin share a complex cyclic depsipeptide scaffold with several highly unusual building blocks and are, due to their unique mode of action, promising leads for antibiotic drug development.

In contrast to dityromycin, the structure of GE82832 has not been fully elucidated. The Crüsemann group has recently sequenced the GE82832 producer and identified a candidate NRP synthetase biosynthetic gene cluster (BGC), which will form the basis of the present studies. They will elucidate the GE82832 structure with advanced NMR and MS/MS experiments.

The candidate BGC will be heterologously expressed for confirmation and to allow in vivo biosynthetic studies. Feeding studies with altered, e.g. halogenated precursors will be carried out to generate unnatural analogues, that will be isolated and characterized to conduct the first systematic SAR studies for this compound class. Furthermore, GE82832 will be used for semisynthetic studies to further extend SARs on this promising group of antibiotics.

Biological activities of the generated compounds will be evaluated in cooperation with P6 and P7, and molecular modeling studies will be conducted in collaboration with P9 utilizing TP2. Semisynthetic variation of GE82832 and biological studies will be performed in collaboration with P3.