Isolation, Total Synthesis and Determination of the Absolute Configuration of Guadinomines; Potent Inhibitors of a Bacterial Type III Secretion System

The structure of guadinomines, new inhibitors of a bacterial Type III secretion system (T3SS) isolated from the cultured broths of Streptomyces sp. K01-0509. The property has been traced to the novel guadinomines A to D, and three of them have been identified as being selective inhibitors of T3SS. In the process of isolation, a new compound, guadinomic acid was detected, occurring as a biosynthetic intermediate. The T3SS is expressed by many Gram-negative pathogens, where it helps deliver effector proteins into the host cell during the infection process. Original structural analysis was elucidated by spectroscopic studies including various NMR experiments. Guadinomines A to D consist of a carbamoylated cyclic guanidinyl moiety, an alkyl chain moiety and an dipeptide moiety in common, while guadinomic acid is a smaller molecule including a carbamoylated cyclic guanidinyl moiety. However, the relative and absolute configurations of these compounds remained to be determined, except for the peptide moiety. Herein, we report the isolation, the total assignment of the configurations of guadinomic acid, guadinomines B and C-2, through the first asymmetric total synthesis of these natural products.