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Compounds Block Spread of Antibiotic Resistance

The success of antibiotics is among modern medicine's great achievements. But microbes have been evolving resistance. Many diseases, including tuberculosis, gonorrhea and childhood ear infections, are now becoming more difficult to treat. Researchers have discovered 2 medications already approved for other uses that can block the transfer of drug resistance genes between bacteria and even kill bacteria that harbor resistance genes. This novel type of antibiotic could potentially be used against multidrug resistant bacteria.

The heavy use of antibiotics allows only those bacteria with the greatest antibiotic resistance to survive and thrive, thus ensuring that future generations of bacteria will have greater drug resistance. Different strains of bacteria can spread drug resistance genes through a process called conjugation. More than 50 years of widespread antibiotic use have thus encouraged the spread of bacteria with resistance to multiple antibiotics.

A team of researchers at the University of North Carolina, Chapel Hill led by Dr. Matthew R. Redinbo set out to see if they could find compounds that inhibit conjugation. Conjugation involves bacteria forming a junction between them and transferring circular pieces of DNA called plasmids. The study, which was funded by NIH's National Cancer Institute (NCI) and National Institute of General Medical Sciences (NIGMS), was published in the July 13, 2007, online edition of Proceedings of the National Academy of Sciences.

The researchers focused on a DNA relaxase, a type of enzyme involved in conjugation, from E. coli. DNA relaxase initiates DNA transfer by nicking one of the plasmid's DNA strands. After analyzing the structure at the enzyme's active site, the researchers hypothesized that chemicals called bisphosphonates might inhibit relaxase activity and therefore block DNA transfer. They tested several bisphosphonates and found that many inhibited DNA relaxase, including 4 that are already clinically approved by the U.S. Food and Drug Administration (FDA) to treat bone loss.

The researchers next tested whether the compounds could prevent living bacterial cells from transferring the plasmids. Two of the clinically approved bisphosphonates, etidronate (Didronel) and clodronate (Bonefos), were both effective not only at preventing DNA transfer but also at killing the cells that harbored the plasmids.

This study shows that bisphosphonates are a potential new class of antibiotics that can prevent the transfer of plasmids, and therefore drug resistance genes, between bacteria. Further research will show whether these compounds are effective in living systems.

— by Harrison Wein, Ph.D.