Phages treat resistant bacterial infection

16 May 2019

BACTERIA

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A 15 year-old cystic fibrosis patient battling life-threatening mycobacterial infection was running out of options... until her doctors tried using viruses to kill the bacteria...

As antibiotic-resistance becomes more commonplace, resorting to entities that have naturally evolved to target bacteria could represent a promising avenue. Bacteriophages - phages for short - infect and replicate inside bacteria, and may kill their host as part of their life cycle. As different phages infect bacteria through different receptors, a mix of multiple phages could also reduce the possibility of resistance.

Now, in a recent paper in the journal Nature Medicine, Rebekah Dedrick, Carlos Guerrero-Bustamante and their team from the University of Pittsburgh report the first use of genetically-engineered phages to target an antibiotic-resistant mycobacterial infection in a patient with cystic fibrosis. Cystic fibrosis is an inherited condition linked to respiratory problems caused by mucus accumulation in the lungs.

The 15 year-old patient, Isabelle Carnell, had received a lung transplant but was left battling a disseminated infection caused by Mycobacterium abscessus (M.abscessus), a relative of the tuberculosis bacterium. 

The Pittsburgh team set about screening the more than 15,000 phages they had catalogued in recent years, looking for any capable of infecting and destroying M.abscessus bacteria.

Their search led first to a phage family that efficiently killed the bacteria isolated from the patient. Then a second phage was identified and genetically engineered to knock out a repressor gene that, left in situ, would have prevented this phage from killing the bacteria it infected. With the gene gone, it was a potent death sentence for the mycobacterial cells. A third type of phage was also isolated and genetically manipulated to introduce a mutation to alter its host range, so it could target M. abscessus more efficiently.

Prepared as a cocktail to minimise the chances of the bacteria becoming resistant to a single phage treatment, the three-phage mix was administered initially intravenously, and then topically, to the patient's operative wounds and the skin lesions produced by her M.abscessus infection.

Following the application, the patient's lung and liver function slowly began to improve, and her skin lesions resolved. Seven months later, M. abscessus was no longer detectable in her bloodstream or sputum, although the team report that low levels are still present at some skin sites. Microbiological experiments suggest the phages are replicating in the patient's body, although there is no evidence that the body is reacting to the phages, or that the bacteria are becoming resistant to the phages. Together, these results suggest this cocktail of phages was able to succeed where eight years of antimycobacterial treatment had failed and treat the infection.

It is possible that the clinical improvements the team have seen could have occurred by chance, although this is extremely unlikely, and this is a finding from a single patient, so it should be interpreted with caution. Nevertheless, the treatment of bacterial infections is in urgent need of new solutions, and this success is another reminder of the power of combining modern technology and pre-existing solutions nature has engineering for herself over millions of years.

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