If you have an ACS member number, please enter it here so we can link this account to your membership. (optional)

ACS values your privacy. By submitting your information, you are gaining access to C&EN and subscribing to our weekly newsletter. We use the information you provide to make your reading experience better, and we will never sell your data to third party members.


Biological Chemistry

A Revamped Vancomycin

Medicinal Chemistry: Modified compound shows promise against hard-to-treat bacteria

by Stu Borman
August 22, 2011 | A version of this story appeared in Volume 89, Issue 34

New Model of Vancomycin
To get to the modified antibiotic from vancomycin, replace the disaccharide (black) with hydrogen to form the aglycone and replace the oxygen in a key amide (red) with nitrogen to form an amidine.
New Model of Vancomycin

Researchers have achieved a key step toward redesigning the antibiotic vancomycin so that it kills some resistant bacteria. The work could lead to drugs effective against difficult-to-treat infections.

Discovered by Eli Lilly & Co. researchers in the 1950s, vancomycin is a glycosylated natural product that has become the antibiotic of last resort for hard-to-treat infections, such as those caused by antibiotic-resistant staphylococcal and enterococcal bacteria.

But eventually bacteria developed resistance to vancomycin, too, in some cases by changing an amide to an ester in a bacterial glycopeptide cell-wall precursor. Antibiotic mechanisms expert Christopher A. Walsh of Harvard Medical School and coworkers showed in the early 1990s that the modified glycopeptide is less likely to interact with one of vancomycin’s oxygens, thereby inhibiting binding of the drug to the glycopeptide and turning off the drug’s antibiotic action.

Now, synthetic chemist Dale L. Boger and coworkers at Scripps Research Institute, in La Jolla, Calif., have turned the tables on these resistant bacteria by synthesizing a form of vancomycin in which an amide containing the interacting oxygen has been changed to an amidine, which lacks oxygen (J. Am. Chem. Soc., DOI: 10.1021/ja207142h). “The thought was floating around for some time” that such a modification could restore efficacy, Walsh says. People would ask at seminars, he adds, “ ‘Why not change the amide?’ My reply was always that it would be a monumental synthetic challenge.”

The researchers simplified the challenge by modifying only vancomycin’s aglycone, which is vancomycin minus its disaccharide group. In in vitro tests, the amidinated aglycon achieves about the same level of activity as vancomycin against antibiotic-sensitive bacteria and retains a similar level of activity against bacteria with the resistant amide-to-ester modification, making it about 1,000 times stronger than the parent compound against those microorganisms.

For the amidinated aglycon to be effective in vivo, however, the disaccharide or a modified version of it would have to be installed, and this would make synthesis of the redesigned vancomycin yet more difficult.

Synthesis of the amidinated aglycon “is a highly creative and rationally targeted approach” to combating bacterial drug resistance, says antibiotic resistance specialist Gerry Wright of McMaster University, in Hamilton, Ontario. “The big challenge will be to figure out if this can be applied in real-life drug discovery efforts.”

The new study “is the culmination of a monumental effort by Boger and his group to resuscitate this antibiotic scaffold against vancomycin-resistant enterococci,” Walsh comments. It “shows medicinal chemistry mastery in this forbiddingly complex scaffold.” It does open the question of whether anyone could make a fully glycosylated amidinated vancomycin analog on a practical scale, but one cannot rule that out, he says.



This article has been sent to the following recipient:

Chemistry matters. Join us to get the news you need.