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BACTERIA: BEWARE!
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NEWS OF THE WEEK
SCIENCE
August 27, 2001
Volume 79, Number 35
CENEAR 79 35 p. 16
ISSN 0009-2347
[Previous Story] [Next Story]

DRUG-RESISTANT BACTERIA TAMED
Small-molecule agent raises hopes for combination drug development

STEPHEN STINSON

A small molecule can render vancomycin-resistant bacteria susceptible to the antibiotic once more, scientists have discovered [Science, 293, 1484 (2001)]. The finding suggests that a synthetic compound might be developed for coadministration with vancomycin in humans.

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Vancomycin is the antibiotic of last resort for antibiotic-resistant infections. Doctors fear that virulent bacteria like Staphylococcus
aureus may also acquire resistance to vancomycin, resulting in a "superbug." Indeed, vancomycin-resistant strains of Enterobacter faecium have already appeared, and S. aureus could obtain the genes from that organism.

The discovery was made by Gabriela Chiosis, formerly of Columbia University and now a research fellow at Memorial Sloan Kettering Cancer Center, New York City, and then Rockefeller University microbiology professor Ivo G. Boneca, now of the Pasteur Institute in Paris.

Vancomycin acts by binding to a sequence of two molecules of D-alanine that bacteria use to build and keep cell walls in repair, causing the cell walls to deteriorate. The bacteria then burst and die. Resistant bacteria have switched to a sequence of D-alanyl-D-lactic acid, which foils vancomycin's binding ability.

Chiosis and Boneca at first screened a combinatorial library of tripeptides to find compounds that catalyze hydrolysis of the resistance-conferring D-alanyl-D-lactic acid sequence. But even the best tripeptides weren't active enough--the bacteria could metabolize them as nutrients. However, they did find that a recurring motif in active compounds was L-proline bound to an amino acid with a nucleophilic side chain.

Based on these leads, the researchers designed and tested a series of prolinol derivatives. The most successful agent was the amide of L-prolinol with -aminocaproic acid. Adding this amide with vancomycin to a culture of resistant E. faecium lowers the amount of the antibiotic needed to inhibit the bacteria's growth by a factor of eight.

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