JULY 30, 2007
VOLUME 4 NO. 13

ADVANCES in MEDICINE

Osteo med castrates drug-resistant bacteria

Drug stops mutant bugs from 'mating,' offers new hope for MRSA



Bacteria spread antibiotic-resistance via relaxase.
Illustration: Scott Lujan, UNC-Chapel Hill

A couple of old osteo drugs could hold the key to fighting deadly antibiotic-resistant bacteria like MRSA, according to a new study in the July 13 Proceedings of the National Academy of Sciences.

A team of US researchers found that clodronate and etidronate, first generation bisphosphonates, block an enzyme in E coli cells that allows bacterial 'mating' and gene transfer. "The surprise was that they also killed the cells carrying the resistance gene," says lead author Matt Redinbo, PhD, biochemist and biophysicist at the University of North Carolina at Chapel Hill. "Although, in retrospect, we shouldn't have been so surprised, because normally if you screw with DNA movement you would cause cell death."

The discovery opens up a slew of possibilities in the fight against antibiotic-resistant bacteria. "This may lead to the ability to selectively kill antibiotic-resistant bacteria in patients, and halt the spread of resistance in clinical settings," says Dr Redinbo. Although the study was done on lab cultures, Dr Redinbo and his team have started an animal study and are currently testing a wider variety of bacteria to see if the bisphosphonates will work on them.

MUTANT BACTERIA
Antibiotic resistance is cause enough for concern that the CDC in the US has designated an entire program to watch for it: the National Antimicrobial Resistance Monitoring System (NARMS). More than 2 million people a year get hospital-acquired infections in the US alone, and 90,000 die. In Canada, an E coli outbreak last September left 14 Ontarians severely ill, while a simultaneous one in the US claimed the lives of three people. Commonly found in human and farm animal intestines, E coli spreads through fecal contamination and poor hygiene.

"We worked with ampicillin-resistant E coli ," says Dr Redinbo. "This bacteria uses the same system to conjugate and spread as a wide variety of infectious bacteria." The key component of that system is an enzyme called relaxase.

When a person gets infected and then treated with antibiotics, a sort of Darwinian natural selection occurs. The weaker bacteria get killed off. The ones that remain have a genetic mutation that allows them to survive. They start spreading that mutation quickly to other cells through conjugation, a sort of mating dance mediated by relaxase.

During conjugation, two bacterial cells, one of which has the antibiotic-resistance gene, get close together and are joined by relaxase. Each cell sends a single strand of its phosphate-rich DNA to bind to a special site on the enzyme. Relaxase then does a strand exchange, sending the resistance gene to the weaker cell and helping the resistance spread through the colony.

The researchers figured that the conjugation phase would be a good time to target the bacteria, hitting it where it hurts, so to speak, with half its DNA hanging out. So they took a closer look at relaxase. "One of my graduate students, Scott Lujan, solved the problem," says a proud Dr Redinbo. "He looked at the crystal structure of the enzyme and predicted that its weakest point would be where it had to accommodate the two DNA strands." Given the high phosphate content of DNA, they suspected that another phosphate-rich compound could block the dual binding site, hence the bisphosphonates.

"Etidronate and clodronate are typically prescribed for bone loss," says Dr Redinbo. "They've been replaced by newer generation bisphosphonates in clinical use. We tested other bisphosphonates that were easier to obtain — clodronate is not commercially available in the US — but they didn't work as well."

Both drugs can have serious side effects, ranging from stomach cramping to birth defects, but Dr Redinbo believes that where there's a will, there's a way. "A possible use is with Staph infections or skin related infections where dosage can be tightly controlled, or perhaps associated with a catheter for a more targeted drug delivery," he suggests.

AS SEEN ON TV
The relatively obscure biochem discovery has already hit the small screen. "This morning, I was on the CBS Early show," says Dr Redinbo.

The scientist quickly discovered that his new-found celebrity comes with a cost, when his phone started ringing off the hook. "I've had calls from people saying 'I've got MRSA, how can I use this drug to stop the infection?'" he says. "I'm not a clinician and the research is still in its early stages, but we're working on translating this work into a mammalian system."

Dr Redinbo and his team have applied for a patent for their discovery and are currently testing out the drugs with other bacteria. "This relaxase system is found in Staphylococcus strains, Acinetobacter strains and other common bacteria," says Dr Redinbo. "These strains cause really prevalent infections, so the hope is that these drugs will either help existing antibiotics or offer a new treatment for antibiotic-resistant bacteria.

 

 

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