Bisphosphonates May Be Key to Overcoming Antibiotic Resistance

By Laura Brasseur

Proceedings of the National Academy of Sciences

A potential breakthrough in the plight of antibiotic resistance emerged recently, when investigators discovered that they could use bisphosphonates to attack the "gatekeeper" of resistance, an enzyme called relaxase, which, to their surprise, interrupted the resistance process before it could get started. The results are published in the (2007; 104:12282-12287).

Matt Redinbo, PhD

The first discovery was the Achilles' heel of the relaxase enzyme that allows "fertile" bacteria to exchange genes for drug resistance. University of North Carolina (UNC) at Chapel Hill graduate student Scott Lujan identified what he thought was the weak link in the resistance process—the point at which relaxase must manage 2 DNA strands simultaneously.

Matt Redinbo, PhD, professor of chemistry, biochemistry, and biophysics at UNC-Chapel Hill, then came up with what he believed would be the perfect "chemical decoy" for heisting the DNA binding site: bisphosphonates, which are currently used to treat bone loss.

Only 2 bisphosphonates were found to be effective in plugging up the DNA binding site and selectively killing the bacterial cells that harbored resistance—etidronate disodium (Didronel) and clodronate (available in Canada, not in the United States).

"Etidronate and clodronate do not have the longer amine-containing side chains that the later-generation bisphosphonates like pamidronate [Aredia] do," Dr Redinbo told IMWR. "These side chains apparently help in disrupting the function of the farnesyl diphosphate synthase enzyme that is the putative target of these drugs in osteoclasts, providing their effect in osteoporosis. The smaller bisphosphonates clodronate and etidronate appear to fit better in the active site of the relaxase, the plasmid enzyme we are targeting in bacteria" (Figure).

Escherichia coli

E coli

The 2 bisphosphonates prevented relaxase from handling DNA inside of bacteria just before they could transfer their drug-resistant genes to other bacteria. Thus far, the results apply only to .

"Relaxases are generally present on mobile plasmids that propagate through bacterial populations and can bring with them antibiotic resistance genes or genes for virulence factors," said Dr Redinbo. "Most bacteria can contain a relaxase because the plasmids that carry them are capable of propagating through an impressively broad range of microbial species, including Gram-positive and Gram-negative strains."

E coli

E coli

E coli

He added that these plasmids can spread between very dissimilar bacterial species. "In other words, plasmids with resistance or virulence genes can move between a nonpathogenic strain, for example, and a pathogenic Enterococcal strain. For those reasons, we are reasonably enthusiastic about the applicability of these methods beyond . Testing species beyond is now under way."

These discoveries may open the door to the selective destruction of antibiotic-resistant bacteria, and close the door on the spread of resistance.

Image courtesy of Scott Lujan, UNC at Chapel Hill

Figure.