Biomimetic strategy harnesses enzyme to make library of potential antibiotics
FULL SIZE - CLICK IMAGE
With the help of an enzyme that turns peptides into macrocyclic molecules, researchers have created a combinatorial library of potential antibiotics, some of which show promising activity against drug-resistant microbes.
Some antibiotics are macrocyclic peptides. Bacteria and fungi make peptide chains that can be transformed into macrocyclic antibiotics with the help of a synthetase enzyme. Now, Christopher T. Walsh, a professor at Harvard Medical School, and colleagues show they can synthesize peptide chains on commercially available polymer beads, then use the thioesterase domain of the enzyme to cyclize the molecules [Nature, 418, 658 (2002)].
Because the thioesterase's activity is unaffected by substitutions in many peptide side chains, it's able to cyclize a wide swath of chemically made peptides. "That increases the potential diversity of linear precursors that can be macrocyclized," Walsh says.
The bead synthesis strategy, coupled with the enzyme's flexibility, allowed the researchers to generate a library of hundreds of variants of the cyclic decapeptide antibiotic tyrocidine A.
Some of the compounds in the library, the Walsh group finds, are more active in killing toxic organisms such as Escherichia coli and Staphylococcus epidermidis, and show less toxicity, than the parent tyrocidine A.
Princeton University chemistry professor and antibiotics expert Daniel Kahne calls the research "an extremely important piece of work."
The authors hope to extend their approach to related families of natural product macrocyclic antibiotics, polyketides, and hybrid peptide/polyketides.