Kicking out Drug Resistance

A new strategy for combating antibiotic resistance could turn back the clock and make old antibiotics useful again.

Bacterial resistance to antibiotics is spreading at an alarming pace. First encountered in hospitals, drug-resistant bacteria such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci now commonly infect healthy people in larger communities, too. In most cases, such bacteria gain the ability to outwit antibiotics from plasmids, tiny circles of DNA that take up residence in bacteria. These plasmids carry genes that encode enzymes that destroy or eliminate a particular antibiotic from bacterial cells. Such resistance-conferring plasmids-which exist apart from the bacteria's own genomic material-can be passed readily between diverse types of bacteria, allowing antibiotic resistance to spread widely and rapidly.

A new and potentially powerful way to battle such plasmid-mediated antibiotic resistance has now been discovered by a team of chemists at the University of Illinois, Urbana-Champaign [J. Am. Chem. Soc., 126, 15402 (2004)]. Assistant professor of chemistry Paul J. Hergenrother and graduate students Johna C. B. DeNap, Jason R. Thomas, and Dinty J. Musk Jr. show that a small molecule can cause drug-resistant bacteria to eliminate their resistance-carrying plasmids. Once denuded of their protective plasmids, the bacteria are again susceptible to the antibiotic.

"This type of intervention to 'cure' a bacterium of its plasmid has never been reported," comments Shahriar Mobashery of the University of Notre Dame, in Indiana. He adds that although the likely toxicity of the particular molecule used-an aminoglycoside-will probably prevent it from moving to the clinic, the Illinois team has clearly demonstrated the viability of their creative strategy to combat antibiotic resistance.

A Hergenrother says his strategy was inspired by a natural phenomenon known as plasmid incompatibility, whereby certain plasmids cannot coexist in the same bacterial cell. Plasmids that replicate themselves in similar ways are forced to compete for various proteins and RNA molecules required for replication. "The end result is that one of these plasmids 'wins' this competition, and the other plasmid cannot replicate," Hergenrother says. Eventually, the unreplicated plasmid is removed from the cell.

Hoping to harness this natural process to eliminate plasmids responsible for antibiotic resistance, Hergenrother's team searched for small molecules that would mimic the function of a small piece of RNA that dictates incompatibility among certain plasmids. They found that the aminoglycoside apramycin does just that, triggering the eviction of an ampicillin-resistance plasmid from bacteria and rendering these bugs susceptible to ampicillin.

Hergenrother is now working to develop compounds that can cause the elimination of plasmids from clinically relevant drug-resistant bacterial strains.