Designer viruses could be new antibiotics

Bacterial infections remain a major threat to human and animal health. Worse still, the catalog of useful antibiotics is decreasing as pathogens develop resistance to these drugs. There are few promising new drugs in the pipeline, but they may not be enough. Multidrug-resistant organisms – also known as "superbugs" – are increasing and many predict a dark future if nothing is done to defend themselves.

Some people think that the solution may lie in the use of artificial bacteriophages – a type of virus that infects bacteria. Two recent studies, both published in the journal Nature Biotechnology, show a promising alternative to small molecule drugs that are now the mainstay of antibiotics.

From basic biology to synthetic biology

Every living organism has developed simple mechanisms to protect itself from harmful pathogens. This innate immune system can be a passive barrier blocking anything that exceeds a certain size or active response that recognizes foreign molecules – such as proteins and DNA – then kills them.

In bacteria, an important component of the immune system is composed of a family of proteins specifically responsible for the degradation of foreign DNA. Each insect produces a set of these proteins that shred the genetic material of viruses and other microorganisms while preserving its genome.

In vertebrates, a more advanced mechanism, called the adaptive immune system, creates a molecular memory of previous attacks and prepares the body for the next wave of infection. This is the principle on which vaccines are built. When introducing harmless pathogenic fragments, adaptive immunity will form specialized killer cells that will then allow a faster and more specific response when in contact with the virulent agent.

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Until recently, people thought that bacteria were too simple to possess adaptive immunity. But in 2007, a group of scientists from the dairy industry showed that bacteria commonly used for cheese and yogurt production could be "vaccinated" by exposure to a virus. Two years earlier, others had noticed similarities between repetitive sections of bacterial genomes and virus DNA. These repetitive sequences, called CRISPRs for "regularly spaced short palindromic repeats," have been known for 20 years, but no one has ever been able to explain their function.

With these two observations, it quickly became clear that bacteria introduced viral DNA fragments into their own genome to protect themselves from subsequent attacks. But it took another five years to get an overview.

In 2012, a German team identified all the pieces and showed how bacteria transcribe exactly viral DNA into a short RNA – usually the messenger molecule – that guides the DNA cleavage protein called Cas9 and he indicates where to cut viral DNA.

It may have been an interesting scientific observation, but in the era of synthetic biology, natural functions can quickly become tools for designers. In the space of two years, many laboratories have demonstrated that by adapting the short RNA guide, any gene could be isolated from a chromosome using the CRISPR system. -Cas9.

Since this breakthrough, hundreds of scientists have used it to manipulate the genome of bacteria, yeasts, worms, cultures, fruit flies, zebrafish, mice, rats or even human cells. Although there are limits, a procedure that took months and used previous technologies – such as genome reproduction or modification – can now be done in a matter of weeks.

Bacterial immunity, rewired

Two teams of scientists, one led by Timothy Lu of the Massachusetts Institute of Technology and the other by Luciano Marriffini of Rockefeller University, each used the CRISPR-Cas9 system to generate their own version of the A technology prototype transforming the defense mechanism of a bacterium into a self-destructive weapon. The main idea of ​​their work was to use genetic engineering to enhance the immunity of the bacteria to produce "boomerang" antibiotics intended only for insects carrying specific genes.

To do this, their teams developed an artificial system CRISPR-Cas9 – capable of removing specific genes – by assembling parts in the laboratory before reintroducing them into a bacterium using viruses. Once injected into the virus, the guide RNA recruits the Cas9 protein to target genes conferring the virus antibiotic resistance or other harmful properties by incorporating viral DNA. Once these genes are removed, the super-bacteria dies or becomes harmless.

Although the method still needs to be improved to become useful for treatment, its ability to specifically kill pathogens has great potential as it can limit their spread to other bacteria.

The fight against antibiotic resistance would not be the only application of these modified viruses. The current small molecule antibiotics also end up killing other healthy bacteria in our body. The new method would incorporate harmless insects, thus minimizing the side effects of antibiotic use.

In recent years, the role of friendly microbes living in the gut has become clearer. The imbalance in species diversity and relative abundance can influence the development of certain conditions, including depression, diabetes, and obesity. In this context, modified viruses that could restore or shape the microbiota (or flora) could significantly improve health.

Luc Henry, Postdoctoral Fellow, EPFL – Swiss Federal Institute of Technology Lausanne – Swiss Federal Institute of Technology Lausanne

This article is republished from The Conversation under a Creative Commons license. Read the original article.