Crushing Bacterial Resistance

Molecules that infiltrate cell walls may reverse drug-immune bugs

THURSDAY, Aug. 23, 2001 (HealthDayNews) -- Getting bacteria to drop a stitch while they knit their cell wall may be the key to outwitting drug-resistant germs, a new study says.

New York scientists report in the Aug. 24 issue of Science that doping harmful bugs with small molecules that thin their outer membrane neutralizes their ability to withstand vancomycin.

Vancomycin resistance is a major worry for doctors because the drug is a treatment of last resort for many serious infections, especially Staphylococcus aureus, a leading cause of severe food poisoning and other infections.

Cases of vancomycin-resistant staph haven't yet been reported; however, at least four samples have shown reduced sensitivity to the drug, and experts say it's only a matter of time before full resistance appears, possibly through contact with other strains of vancomycin-resistant microbes.

A 1998 report from the Centers for Disease Control and Prevention (CDC) says 23.9 percent of all Enterococci bacteria were resistant to vancomycin.

Vancomycin attacks germs by binding to their outer walls and causing them literally to explode. To overcome this unpleasant end, certain strains of germs have developed a defense: By altering the molecular ingredients of their membrane, they foil vancomycin's ability to bind to the wall, reducing its antibacterial powers about 1,000-fold.

Chemist Gabriela Chiosis wondered if she could restore susceptibility to vancomycin by breaking up the substitute sections of a resistant germs' membrane. Chiosis, then at Columbia University, and colleague Ivo Boneca, of Rockefeller University in New York, screened a library of candidate molecules, coming up with three small proteins as possible candidates to cleave the cell wall. One was fairly potent, so they synthesized a similar compound, which they called SProC5, that was twice as effective.

Testing it on a strain of vancomycin-resistant bugs known as Enterococcus faecium, the researchers saw that SProC5 alone wasn't enough to kill the bacteria. But when combined with vancomycin, the number of microbes dropped radically. "If you just use the small molecule you don't see anything. You need them combined," says Chiosis, who now works at Memorial Sloan-Kettering Cancer Center in Manhattan.

Chiosis says the proteins don't allow Enterococcus -- and presumably related organisms -- to knit a thick enough cell wall to defend themselves against vancomycin, offering a second prong of attack.

The researchers didn't test the small molecules for toxicity, so it's not clear whether they would be safe in humans. Columbia and Rockefeller universities filed a joint patent application that will allow them to license SProC5 to drug companies, Chiosis says.

In a second study, appearing in the online issue of Science, scientists led by Princeton University biochemist Daniel Kahne found a gene, yfgL, that makes Escherichia coli bacteria immune to vancomycin-like drugs.

Again using small molecules as bullets, the researchers found that by blocking yfgL they could promote susceptibility to antibiotics. But while vancomycin-like drugs typically stop microbes by slowing their division, genetically altered germs were wiped out quickly by the compounds.

What To Do: For more on drug resistance, try the CDC or this article from Scientific American. To learn more about staph infections, visit the Food and Drug Administration.

SOURCES: Interview with Gabriela Chiosis, Ph.D., senior research scientist, Memorial Sloan-Kettering Cancer Center, New York City; Aug. 24, 2001 Science; Aug. 23, 2001 Sciencexpress
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