Scientists Identify Drugs to Combat Antibiotic Resistance

Scientists at the University of North Carolina-Chapel Hill have developed a way to slow the spread of antibiotic resistance through bacterial populations, which may lead to more sophisticated treatments for bacterial infections. Their research has been published by the Proceedings of the National Academy of Sciences.

Bacterial genes for antibiotic resistance are generally carried on plasmids -- small, circular pieces of DNA external to the regular bacterial genome -- which can be passed on from cell to cell through a process called conjugation. This means that, for instance, if only a few cells in an infection are resistant to an antibiotic, they can pass the genes for resistance along to other cells as well as to their descendents. If there are strains with different antibiotic resistances present in a population, conjugation can also lead to the formation of hard-to-treat multidrug resistant strains. In their new paper, however, the Chapel Hill researchers suggest a possible treatment to inhibit the transmission of resistant genes.

The enzyme DNA relaxase was previously identified as a necessary and important component for conjugation in bacteria. The Chapel Hill team studied the structure of the enzyme, and hypothesized that part of the enzyme might be vulnerable to inhibition by chemicals called biphosphonates. The team tested a number of different biphosphonates by adding them to blended cultures of antibiotic resistant and non-resistant E. coli. They then added an antibiotic and determined how many cells lived, and therefore, how many carried the antibiotic resistance genes. It was found that a significantly smaller percentage of bacteria survived when certain biphosphonates were added, indicating that those chemicals did inhibit the transfer of resistance genes between cells. The researchers also found that effective biphosphonates selectively killed some of the plasmid containing cells, but did not fully investigate the mechanism by which they did so.

The biphosphonates clodronate and etidronate, which are both already used as treatments for bone loss in humans and can be administered in high dosages, were found to be effective at inhibiting conjugation in bacteria in vitro. The authors suggest that it may be possible to use the drugs to treat some infections alone (to kill resistant cells and reduce the chances of transmission of resistant strains), or in conjunction with antibiotics as a sort of antimicrobial cocktail. Novel use of biphosphonates as antimicrobial therapies may not only offer important tools to doctors treating infections, but also help prolong the utility of currently available antibiotics.

References:

Scott Lujan et al., "Disrupting antibiotic resistance propagation by inhibiting the conjugative DNA relaxase." Abstract (and PDF of research paper) available at: http://www.pnas.org/cgi/content/abstract/0702760104v1