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August 18, 2011
Article Updated August 18, 2011, 4:20 PM

Overcoming Antibiotic Resistance

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

Stu Borman

To get to the modified antibiotic from the natural product (shown), 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.
To get to the modified antibiotic from the natural product (shown), 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.
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Researchers have achieved a key step toward a long-sought goal: redesigning the antibiotic vancomycin so that it kills some bacteria that have become resistant to it. 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 glycopeptide cell-wall precursor. Antibiotic mechanisms expert Christopher A. Walsh of Harvard Medical School and coworkers showed 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). Other researchers had proposed that such a modification could restore vancomycin’s efficacy against resistant bacteria, but Boger’s is the first group to create the modified vancomycin, which is difficult to synthesize.

The researchers simplified the challenge by modifying only vancomycin’s aglycon, 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 combatting bacterial drug resistance, says antibiotic-resistance specialist Gerry Wright of McMaster University, Hamilton, Ontario, Canada. 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.

Chemical & Engineering News
ISSN 0009-2347
Copyright © 2011 American Chemical Society
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