Silver enhances antibiotic activity against gram-negative bacteria in mice

The use of silver in medicine is as old as western medicine itself. Hippocrates is known to have used it to treat ulcers and wounds, the Romans almost certainly knew of its healing properties, its use continued through the middle ages and up to the present day. In the antibiotic age, interest in silver may have waned a little. But with urgent need to fight antibiotic-resistant bacteria, there is resurgence in its uses.

The reason is that silver can kill bacteria selectively and, more importantly, bacteria are unable to develop resistance against it. Despite silver’s long medical history, we do not know how it operates. A paper published last Thursday in the journal Science Translational Medicine sheds some light on silver’s success against bacteria. The most important find is that silver – unlike most antibiotics – works in more than one way. This is perhaps why bacteria are not able to build resistance to silver.

Here is silver’s multi-pronged approach: first, silver sticks very strongly to sulfur, found in parts of proteins. These sulfur groups normally bond to each other in proteins, holding them together and keeping the protein folded up in its correct shape. But if silver interacts with sulfur then the protein cannot fold correctly, and thus it cannot do its job. Next silver interferes with how bacteria use iron. Iron is often held in the places it is needed by binding to sulfur. And since silver also interacts with sulfur it stops the iron doing so. Finally, silver causes bacteria to produce extremely toxic substances called reactive oxygen species. These go on to cause damage inside the cell, harming the DNA, proteins and even the membranes that surround cells.

The net result of this silver onslaught is bacteria with severely damaged defences. Most importantly the membranes and walls that surround it are leakier after the silver treatment. Once weakened, they are much more susceptible to conventional antibiotics. James Collins, at Boston University, who led the research showed that with added silver, less antibiotic drug is needed to kill the bugs. A great result in itself, but it gets better. Silver also reverses antibiotic resistance of E. coli bacteria making them, once more, susceptible to tetracycline.

These experiments not only worked in a Petri dish. When silver was added to standard antibiotics such as gentamicin and vancomycin, Collins could treat E. coli infections in the bladder and abdomens of mice. Normally these drugs have little effect on E. coli infections because they are designed to attack a completely separate class of bacteria.

Bacteria are broadly classified into two groups called Gram-negative or Gram-positive. Gram-negatives have an extra cell membrane that protects the bacteria, which means that it is much more difficult for some antibiotics, such as gentamicin and vancomycin, to penetrate the cell. It seems that silver negates this advantage and allows even weaker drugs to do their jobs. Finally, Collins showed that the mice themselves remain unharmed by silver. If he is able to repeat this work in humans, then he may actually have a “silver bullet” for antibiotic resistance.