INDIANA U. (US) — The discovery of two genes that encode repressors in MRSA (Staphylococcus aureus) opens new avenues for controlling the increasingly drug-resistant bacterium.
“We need to come up with new targets for antibacterial agents,” says David Giedroc, professor of chemistry at Indiana University.
“Staph is becoming more and more multi-drug resistant, and both of the systems we discovered are promising.”
The research is reported in the Journal of Biological Chemistry.
MRSA, or multidrug-resistant Staphylococcus aureus, is the primary cause of nosocomial infections in the U.S., those that are the result of treatment in a hospital.
About 350,000 infections were reported last year, about 20 percent of which resulted in fatalities, according to the Centers for Disease Control. One to two percent of the U.S. population has MRSA in their noses, a preferred colonization spot.
One of the newly discovered repressors, CsoR (Copper-sensitive operon Repressor), regulates the expression of copper resistance genes, and is related to a CsoR previously discovered that causes tuberculosis in humans.
When the bacterium is exposed to excess copper, the repressor binds copper and falls away from the bacterial genome to which it is bound, making it possible for the copper resistance genes to be turned on.
Copper is commonly used to kill bacteria and in its presence, a bacterium is well served by expressing genes that help it sequester and export extra copper before the metal can do any real damage.
The other repressor, CstR (CsoR-like sulfurtransferase Repressor), which can react with various forms of sulfur, appears to prevent the transcription of a series of sulfur assimilation genes with similar genes in other species.
The two repressors—and the gene systems they regulate—are possible new drug targets for controlling Staph growth.
A drug could hypothetically target either of the repressors, causing bacteria to become unresponsive to toxic copper levels or incapable of properly integrating sulfur into their cells.
“One thing you could do is prevent the repressors from coming off the DNA in the first place,” Giedroc says, “although I think that’s probably a long shot.
“I think the repressors are one step removed from where you’d like to have the action. At this point I think the better targets are going to be the genes they are regulating.”
Giedroc says he hopes one of the sulfur utilization genes controlled by CstR turns out to be an effective drug target.
“The metabolic process by which sulfur is assimilated is a proven drug target in Mycobacterium tuberculosis,” Giedroc says. “We see no reason why this can’t be the case for Staphylococcus aureus.”
Researchers from Vanderbilt University and the University of Georgia contributed to the study that was funded by from the National Institutes of Health, the Southeastern Regional Center of Excellence for Emerging Infections and Biodefense, and the American Heart Association.
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