A key problem in the synthesis was how to create thiazoles – five-membered rings containing a sulphur atom and a nitrogen atom. They begin with a cysteine fragment, and convert it to a thiazole via a cyclodehydration reaction (creating a cyclic fragment and eliminating an H2O molecule in the process). This reaction often requires a stoichiometric reagent (a participating molecule that is used up during the reaction), but Dr Walczak and his team have used a molybdenum catalyst. This is less wasteful and more efficient than using a stoichiometric reagent, since only a small amount of catalyst is required – it can repeat the reaction multiple times and can be recovered at the end of the reaction.
The full synthesis uses 15 steps, and is a process of building up a long string of molecular fragments from small starting blocks. The only by-product is water, making it environmentally-friendly, and the approach can easily be adapted to synthesise different types of thiopeptide antiobiotics.
"There is a constant demand for new antibiotics because of the emergence of bacterial strains resistant to old antibiotics", says Dr Walczak. "This is especially true as the number of infections and deaths associated with antibiotic resistant organisms increases throughout the world. Thiopeptides represent a novel class of antibiotics capable of addressing bacterial multidrug resistance."
"We think it will be possible to use thiopeptides themselves or other molecules inspired by thiopeptides in the clinic."
This article is free to read in our open access, flagship journal Chemical Science: Siddhartha Akasapu et al., Chem. Sci., 2019, Accepted Manuscript. DOI: 10.1039/C8SC04885A. You can access all of our ChemSci Picks in this article collection. Read more like this