With viruses such as the new Middle East novel coronavirus and the H7N9 bird flu in the news because of their deadly spread, researchers have found another way that viruses are putting human health at risk. Bacteria, like humans, can be infected with viruses that hijack a cell's internal machinery to make more viruses. These bacterial viruses, called bacteriophages, or phages, only infect bacteria and were thought to not have any effect on human health. Companies even wanted to use phages to infect and kill bacteria in the meat supply industry to make it safer for humans. But new research is showing a way through which these viruses can indirectly and adversely impact human health and even public policy.

Scientists at the Wyss Institute at Harvard have found that these bacteria, which are only infecting viruses, can transfer antibiotic resistance to infected bacteria. What's scary in the looming prospect of superbugs losing susceptibility to last line of defense antibiotics is that these viruses can confer resistance to anti-bacterial compounds that the bacteria have never been exposed to before. They propose in new research that this may be a reason for the sudden emergence of multi-drug resistant bacterial strains and offers a new target for treatments.

"The results mean that the antibiotic-resistance situation is even more troubling than we thought," said senior author Jim Collins, Ph.D., a pioneer of synthetic biology and core faculty member at the Wyss Institute for Biologically Inspired Engineering.

The researchers knew that these phages are abundant in the gut of animals, as bacteria are, and that they can ferry bacterial genes between infected individual bacterial cells. While most previous research has solely focused on bacterial acquisition of resistance and transfer of genes between bacteria, no one has looked at the role that phages play in the process of antibiotic resistance.

A phage attached to a bacteria. (The Dennehy Lab, Queens College)

The researchers decided to see if phages alone could confer antibiotic resistance between animals. They gave mice either ciprofloxacin (Cipro) or ampicillin, which are commonly prescribed antibiotics for infections in people. After eight weeks the researchers harvested the virus from the mouse feces and then analyzed the genes contained within the viruses by genetic sequencing. By comparing the viral DNA to databases of antibiotic resistance genes, they found that the viruses contained more genes that conferred resistance to antibiotics than chance alone would account for.

The treatment showed that when mice were treated with ampicillin, the phages contained more genes for resistance to penicillin- and ampicillin-related drugs. And similarly, a virus found in ciprofloxacin-treated mice had contained more genes that can give bacteria the ability to resist drugs in the same class of antibiotics. "When we treat mice with certain classes of drugs, we see enrichment of resistance genes to those drug classes," said Dr. Sheetal Modi, lead researcher on the project.

To have proof of the concept, the researchers wanted to show that the viruses not only contained bacterial antibiotic resistance genes, but also could transfer them to other bacteria. By isolating the virus from antibiotic-treated and untreated mice, and exposing gut bacteria from other untreated mice, the scientists found that the viruses can transfer antibiotic resistance. Viruses from ampicillin-treated mice increased ampicillin resistance in infected bacteria by more than three times and viruses from ciprofloxacin-treated mice increased resistance by double. And if this wasn't bad enough, the viruses also carried other genes for antibiotic resistance from antibiotics that mice were not treated with.

As we learn more about the ecology of our gut and discover the delicate balance that exists to keep us healthy, we need to research the complex interplay at work and how it affects our microbiome, the trillions of bacteria that inhabit our bodies in a symbiotic and commensal relationship. "Antibiotic resistance is as pressing a global health problem as they come, and to fight it, it's critical to understand it," said Don Ingber, M.D., Ph.D., Wyss Institute Founding Director. "Jim's novel findings offer a previously unknown way to approach this problem by targeting the phage that live in our intestine, rather than the pathogens themselves."

Source: Modi S, Lee H, Spina C, Collins J. Antibiotic treatment expands the resistance reservoir and ecological network of the phage metagenome. Nature. 2013.