New research shows that low doses of silver can massively boost the effect of antibiotics on bacteria, making them up to 1,000 times more sensitive to the drugs. The researchers hope their discovery will give new life to old antibiotics, including those to which microbes have become resistant.

Jim Collins, of the Wyss Institute for Biologically Inspired Engineering at Harvard University, and colleagues, report their findings in a paper published online in Science Translational Medicine on 19 June.

They found not only did silver boost the ability of a broad range of commonly used antibiotics so as to stop mice dying of otherwise lethal infections, but it made at least one resistant bacterium succumb to antibiotics again.

The addition of silver also broadened the effect of vancomycin, an antibiotic that is usually only effective at killing Gram-positive bacteria like Staph and Strep; aided by silver it killed Gram-negative bacteria such as those that cause food poisoning and dangerous hospital-acquired infections.

(These two types of bacteria acquired the name Gram-positive or Gram-negative because they react differently to a stain test developed in the 1800s by Hans Christian Gram: one group retains the stain and the other does not).

Plus the team also found that silver helped deal with two kinds of infection that usually require repeated trips to the clinic for antibiotic treatment. One is caused by biofilms, slimy layers of microbes that coat catheters and prosthetic joints, and the other is caused by bacteria that lie dormant during antibiotic treatment and then resurge when it finishes, causing recurrent infections.

In a statement, Collins, a pioneer of synthetic biology and Core Faculty member at the Wyss Institute, says their findings suggest silver could play a really valuable role as an adjunct to current antibiotics.

Because it is proving very difficult for drug companies to find new drugs to tackle the rising problem of antibiotic-resistant bacteria, scientists like Collins and his team are looking back at some of the older infection-fighting methods, even those used before antibiotics became common in the 1940s.

Silver has long been used to prevent and treat infections, but exactly how it works has been somewhat of a mystery.

So the team decided to have a closer look with new tools and find out.

They treated normal and mutant strains of E. coli with a compound containing silver, looked at them through an electron microscope, and ran some biochemical tests.

They found that the silver compound made the bacteria produce more reactive oxygen species (ROS), chemicals that all living cells make as a byproduct of metabolism.

ROS play an important role in helping cells carry out normal functions. But in excess, they can damage proteins and DNA, and also the cell’s membrane.

The silver compound also caused the cell membrane to become leaky.

The team wondered if all these effects together might make the bacteria less able to withstand antibiotics.

And that is what they found: even at small doses, silver made the E. coli 10 to 1,000 times more sensitive to gentamycin, ofloxacin, and ampicillin, three widely used antibiotics.

First author Ruben Morones-Ramirez, until recently a postdoctoral fellow at the Wyss Institute, and now a professor at Universidad Autònoma de Nuevo Leon in Mexico, says:

“If you know the mechanism, you can have much more success making combinatorial therapies.”

For the next part of their study the team turned to mice.

They found silver made a urinary tract infection of E. coli that was resistant to tetracycline succumb to the antibiotic.

And in mice with life-threatening peritonitis (an inflammation that occurs as a result of infection of the thin layer of tissue lining the inside of the abdomen), silver helped vancomycin save the lives of 90% of them. In contrast, when vancomycin was used without silver, 90% of the mice died.

The team then tested the doses of silver they were using to check they were not toxic. They found the levels they were using were far too low to harm the mice, and they also did not harm human cells.

While this suggests the doses they used would be safe to give either orally or by injection in human patients, Collins, who also leads the Center of Synthetic Biology at Boston University, says:

“We’re keen to explore how smart drug-delivery nanotechnologies being developed at the Wyss could help deliver effective but nontoxic levels of silver to sites of infection.”

Funds from the National Institutes of Health, Howard Hughes Medical Institute, and the Wyss Institute helped finance the study.

In this study it is the chemical property of silver that helps to make bacteria more sensitive to antibiotics. In another intriguing study published earlier this year, scientists showed how insect wings kill bacteria on contact, using only their physical structure, unaided by chemical or biological agents. Tiny nanopatters on the insect’s wing surface tear the microorganisms apart.

Written by Catharine Paddock PhD