Enzymatic Cleavage of the Fatty Acid Side Chain

1 Enzymatic Cleavage of the Fatty Acid Side Chain 

None of the A21978Ci 3 factors was sufficiently promising to develop as a clinical candidate, so Lilly explored methods to chemically modify the 

Daptomycin R = n-decanoyl A21978C, R = anteisoundecanoyl A21978C2 R = isododecanoyl A21978C3 R = anteisotridecanoyl 

A21978C core peptide. Lilly scientists reasoned that, if they could remove the lipid side chain, it would open up the molecule to facile SAR studies with other lipid side chains. They discovered that Actinoplanes utahensis produced a deacylase enzyme that cleaved the lipid side chains from all A21978C factors.10 This provided a robust route to prepare the core peptide for chemical modification. 

In retrospect, neither of these important antimicrobial agents could have been developed if Lilly did not have a fully integrated natural products discovery group that included scientists dedicated to bioconversions of natural products and medicinal chemists dedicated to modifying complex cyclic peptides and other secondary metabolites. This may be a lesson learned to help guide antibiotic discovery and development in the 21st century. 

---