Synthesis and Study of Peptidic Bacterial Siderophores

Abstract

Siderophores are natural products found in many organisms, such as bacteria, which show high binding affinities for metals. Siderophores are an essential component of bacterial metabolism as they allow uptake of metal ions into the cells. The synthesis and study of siderophores are therefore useful in the understanding of bacterial metabolism and for the development of future antibiotics. This thesis will focus on the synthesis and investigation of two nonribosomal peptide bacterial siderophores. Firstly, we will discuss our work on mirubactin C, an NRPs siderophore isolated from Actinobacteria sp. DEM60616 which was thought to inhibit bacterial lipoteichoic acid synthase (ltaS). Both the natural (R,R)- and unnatural (S,S)- enantiomers of mirubactin C were synthesised over 12 steps in 12% overall yield, with absolute stereochemistry confirmed by Marfey’s analysis, and the biological activity of both synthetic enantiomers versus the isolated natural product was examined (Scheme 1). Scheme 1. Synthesis of mirubactin C, including biological activity testing. Secondly, we have worked towards the synthesis of madurastatin C1, a siderophore isolated from Actinomadura sp. DEM31376. We present our construction of the complete backbone of madurastatin C1 over 14 steps with a 17% overall yield, and our exploration of the final steps involving oxazoline formation and global deprotection (Scheme 2). Scheme 2. Towards the synthesis of madurastatin C1. N.B. Chemical symbols and formulas unable to be shown in the abstract.