Is the centuries-old strategy of using bacteria-eating viruses to fight disease making a comeback?
The word “superbug” is a familiar term. We now know that the overuse of antibiotics has contributed to creating these tiny, life-threatening monsters. The hunt is on for new antibiotics to fight these superbugs, but it cannot completely resolve the issue of multi-drug-resistant (MDR) bacteria. Bacteria are dynamic systems; continuously evolving to survive by gaining resistance to new antibiotics almost as fast as we can create them. Alternative approaches are necessary to combat MDR, and phage therapy may be the top candidate.
A phage, also known as a bacteriophage, is a virus that infects and replicates within bacteria, and phage therapy is the therapeutic use of bacteriophages to treat infectious disease. The phage is often an obligate killer of its host, meaning the phage kills its host bacterial cell in order to reproduce. Bacteriophages are widely distributed in locations populated by their hosts, including the human body, seawater and soil. The largest population among different organisms on Earth belongs to phages, with an estimated number of viral SpeTarparticles around 10 31.
Phage therapy is not a new concept. It dates back to the pre-penicillin era, when French-Canadian microbiologist Félix d’Herelle used phages to cure four patients of dysentery in 1919. However, the interest in phage therapy was dampened with the discovery of conventional antibiotics and their effectiveness in treatment of infectious disease. It was revived decades later with the first scientific phage summit in 2004. The burgeoning interest in phages led to, among other things, the revolutionary gene editing tool known as CRISPR Cas-9.
Phage characteristics: Specific, adaptable and easy to find
What have we learned about phages? Well, they are relatively specific. They typically have a very narrow antibacterial spectrum limited to one single species of bacteria, or even a single strain within a species. Their specificity can make them tricky to use, but they have the benefit very low collateral damage outside of their chosen target. This stands in sharp contrast with common antimicrobial drugs that do not distinguish between infectious and harmless bacteria, resulting in a greater disturbance of microbiota.
Phages are also dynamic and highly adaptable, much like their hosts. If the bacteria mutates to resist the phage, the phage counters with mutations of its own. This enable us to beat the superbugs at their own game, fighting fire with fire. Although there is a potential for direct interaction with the human immune system, these concerns are no greater than those with biologics, viral vectors used to deliver in gene therapies or live-attenuated vaccines (vaccines that have been genetically modified to make then less virulent or harmless.
What’s more, phages are easy to discover and characterized due to the use of next-gen imaging and genetic tools. After the first phage was discovered, in 1915, only a handful of phages were studied in great detail. The recent renaissance seen in phage biology has been triggered due to a growing awareness of the number of phages in all bacterial dominated environments revealed by epiflourescent and electron microscopy, molecular studies and the genomes of bacteria following whole genome sequencing projects.
Phages and modern medicine
An ideal candidate for phage therapy is an obligately lytic phage with a high potential to reach and then kill bacteria. Like any other drug candidate, phages must display a good pharmacokinetic profile with optimal absorption, distribution, and half-life (survival in a live biologic system). In addition, they must have sufficient stability under typical storage conditions and temperatures. Most importantly, they need to be fully sequenced to ensure absence of undesirable genes and low ability for transduction (ability to transfer gene from one bacteria to other).
There is some resistance in modern medicine to phage therapy, which may stem from unfamiliarity or from guilt by association to the infectious viral family. After all, phages are viruses. The word can be frightening to consumers because it is reminds one of past mass casualties or present infectious diseases such as the flu and HIV. It may not be that easy, therefore, for a drug developer to convince the public to embrace phage therapies. Although there are several clinical trials currently ongoing, ListshieldTM is the only FDA approved phage therapy. It is used as a food additive and kills Listeria monocytogenes, one of the most virulent foodborne pathogens and a cause of meningitis. In the absence of urgent corrective actions to limit overuse of antibiotics and insufficient investment in research for new and innovative weapons against superbugs, the world is heading toward an era in which many common infections will have no cure. With advances in gene editing technology (including CRISPR–Cas9, the genome editing derived from a bacteriophage), we have the necessary tools to investigate the genetic relationship between phages and their bacterial hosts. These tools can also be used to characterize, optimize and select phages for relevant diseases.
(The next installment in our continuing series about phage therapy looks more closely at how pages evolve in nature)