Published online 2 March 2009 | Nature | doi:10.1038/news.2009.131

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Engineered viruses fight bacteria

Viruses that target bacteria could help give antibiotics a boost.

BacteriophageAn engineered phage renders E. coli more susceptible to DNA-damaging drugs.MedicalRF.com / Science Photo Library

Biologists have engineered viruses to weaken the bacteria they infect, leaving the bugs more vulnerable to antibiotics. With more bacteria becoming resistant to the most commonly used antibiotics, the viral approach could extend the useful lifetime of these drugs.

The notion of fighting infection by harnessing the viruses that infect and kill bacteria dates back nearly a century. Doctors in the former Soviet Union routinely prescribed a cocktail of such viruses — called 'bacteriophages' or just 'phages'. But the treatment never caught on in the West, where it was largely abandoned when antibiotics emerged on the scene.

Since that time, researchers have become trapped in an accelerating arms race to develop new drugs against antibiotic-resistant bacteria, leading some to turn to the alternative approach of 'phage therapy'. Several companies are now developing such therapies, and in 2006, the US Food and Drug Administration approved a bacteriophage that could be sprayed onto luncheon meats to kill the bacterium Listeria monocytogenes. This bacterium causes listeriosis — a rare but sometimes fatal infection that can be particularly dangerous for those with a weak immune system, as well as pregnant women and their unborn babies.

To kill without killing

Previous approaches to phage therapy usually relied on bacteriophages that eventually burst open the infected bacteria, killing the cell and releasing more phages to scout for new hosts. But bacteria under this kind of direct attack quickly evolve to become resistant to the phage.

Bioengineer James Collins of Boston University in Massachusetts and his then graduate student, Timothy Lu, decided to take a different tack. Instead of using lethal viruses, they engineered their viruses to just weaken the bacteria, making them more susceptible to antibiotics.

Lu and Collins genetically engineered a phage called M13, which does not cause infected cells to explode, to produce a bacterial protein called lexA3 — which impairs a bacterium's ability to repair damaged DNA. When the modified M13 phage infects a bacterium, in this case Escherichia coli, it produces lexA3, which renders the bacterium more vulnerable to DNA-damaging drugs.

The researchers found that the phage increased the ability of the antibiotic ofloxacin to kill E. coli grown in culture, even when the bacteria were resistant to the antibiotic on its own. The findings suggest that this type of phage therapy could rejuvenate antibiotics that have been deemed no longer effective.

Lingering doubts

Results in mice were also promising: 80% of animals that received both ofloxacin and the modified M13 phage survived infection with a disease-causing strain of E. coli, compared with only a 20% survival rate among infected mice treated with the antibiotic alone.

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"These findings may be generally important in the control of bacterial infections," says Shigenobu Matsuzaki, a microbiologist at Kochi Medical School in Japan. But it is likely to be a long time before such techniques can be used in the clinic, Matsuzaki adds.

Despite its long history, there are lingering concerns about phage therapy. The treatment could trigger an unwanted immune response, for example, or some phages may not survive the trip through the human body to their target cells.

In addition, bacteriophages are notoriously picky about their hosts. In the past, a doctor would administer a cocktail of different phages in the hope that one of them would target the bacterium infecting their patient. But unless a cocktail of engineered viruses can be created, doctors would need to know what particular strain of bacterium is responsible for the infection before starting treatment. 

  • References

    1. Lu, T. K. & Collins, J. J. Proc. Natl Acad. Sci. USA doi:10.1073/pnas.0800442106 (2009).

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  • #60711

    The companies developing phage products seek money for research and trials!

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