February 28, 2011

New Approach to Fighting Staph Infections

Scanning electron microscope image showing lumps of purple spherical bacteria Clumps of methicillin-resistant Staphylococcus aureus bacteria. Janice Haney Carr, U.S. Centers for Disease Control and Prevention.

Researchers have identified a small molecule that can inhibit methicillin-resistant Staphylococcus aureus (MRSA), a growing public health problem. The discovery may eventually open the door to a new class of antibiotics to combat MRSA.

Decades ago, doctors used penicillin to treat infections with the S. aureus bacterium, commonly known as staph. When S. aureus developed resistance to the antibiotic, doctors turned to methicillin. In 1961, scientists identified the first strains of S. aureus bacteria that resisted methicillin.

A research team led by Dr. Paul Dunman at the University of Rochester Medical Center, New York, set out to develop a new approach for combating MRSA. Their work was partly supported by NIH’s National Institute of Allergy and Infectious Diseases (NIAID).

The researchers focused on messenger RNA (mRNA) molecules — transient copies of genes that cells use to carry instructions to the cells' protein-making machinery. MRSA cells must make different mRNA molecules at different stages of growth and virulence, the scientists reasoned. Therefore, the bacteria's equipment for RNA processing and degradation machinery might be vulnerable to attack. The experiments were described online on February 10, 2011, in the journal PLoS Pathogens.

The researchers first looked at mRNA production and degradation during different growth stages in the laboratory. Among the genes whose expression correlated with mRNA degradation, they found, was a component of ribonuclease P (RNase P) called RnpA. RNase P helps process certain RNA molecules. RnpA struck the researchers as an interesting candidate because RNase P is ubiquitous in the bacteria but unique in that it’s made up of both RNA and protein.

The researchers screened almost 30,000 compounds looking for one that interfered with RnpA’s ability to degrade RNA in the laboratory. They found 14 molecules that cut the enzyme's activity by at least 50%. One of the compounds, called RNPA1000, didn’t inhibit other commercially available RNA-degrading enzymes, which suggested that RNPA1000 might be specific to RnpA.

Further experiments showed that RNPA1000 inhibits S. aureus growth in the laboratory. It also proved effective against S. aureus in biofilms — complex, multi-layered microbial communities that are resistant to antimicrobial agents and notoriously difficult to treat.

When tested in infected mice, RNPA1000 saved the lives of up to half the animals. Tests with human cells, however, suggested that the compound might be toxic to people. The researchers are now working to develop related compounds that are more effective and less toxic to human cells.

"This is a great starting point," Dunman says. "We've identified a compound that is very active against RnpA, and now we can use chemistry to try to increase its potency, as well as make it less toxic to human cells. We've gotten a lead from the drug screen, and now we’re building a better molecule."

— by Harrison Wein, Ph.D.

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