How To Reach C&ENACS Membership Number


August 12, 2002
Volume 80, Number 32
CENEAR 80 32 p. 10
ISSN 0009-2347


Biomimetic strategy harnesses enzyme to make library of potential antibiotics



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.


Chemical & Engineering News
Copyright © 2002 American Chemical Society

Related Stories
[C&EN, May 13, 2002]

Vancomycin derivative kills bacteria differently
[C&EN, April 19, 1999 ]

[C&EN, Oct. 30, 2000]

Related Person
E-mail this article to a friend
Print this article
E-mail the editor

Home | Table of Contents | Today's Headlines | Business | Government & Policy | Science & Technology | C&EN Classifieds
About C&EN | How To Reach Us | How to Advertise | Editorial Calendar | Email Webmaster

Chemical & Engineering News
Copyright © 2002 American Chemical Society. All rights reserved.
• (202) 872-4600 • (800) 227-5558

CASChemPortChemCenterPubs Page