Viruses can work against antibiotic-resistant bacteria, new research shows

The new research focused on a particular protein used by bacteriophages (representative).

Viruses called bacteriophages or phages target bacteria but cannot infect humans or other higher organisms. Phages inject their DNA into the bacterial cell, multiply to large numbers using the host’s resources, and then burst out to infect more bacteria in the environment.

Essentially, they are a naturally occurring, self-replicating and specific antibiotic. Its use against bacteria was discovered more than 100 years ago and was largely sidelined in favor of antibiotics.

Our new research looked at a particular protein used by phages to evade bacteria’s natural defenses. We discovered that this protein has an essential control function by binding to DNA and RNA.

This increased understanding is an important step toward the use of phages against bacterial pathogens in human healthcare or agriculture.

Bacterial defense systems

There are hurdles to using phages to target bacteria. Just as our bodies have immune mechanisms to fight viruses, bacteria have also developed a defense mechanism against phage infections.

One such defense is “clustered regularly spaced short palindromic repeats,” i.e CRISPRnow better known for its applications in medicine and biotechnology. CRISPR systems generally act like ‘molecular scissors’ by cutting DNA into pieces, whether in a laboratory or, in nature, in a bacterium to destroy a phage.

Imagine you have a phage against an antibiotic-resistant bacterial infection. The only thing standing in the way of the phage killing the bacteria and eradicating the infection could be the bacteria’s CRISPR defenses, rendering the phages useless as an antimicrobial agent.

That’s where it becomes important to know as much as possible about phage counterdefense. We are conducting research into so-called anti-CRISPRs: proteins or other molecules that use phages to inhibit CRISPR.

A bacterium that has CRISPR may be able to prevent a phage from infecting. But if the phage has the right anti-CRISPR, it can neutralize this defense and kill the bacteria anyway.

The importance of anti-CRISPRs

Us recent research focused on how an anti-CRISPR response is controlled.

When faced with a powerful CRISPR defense, phages automatically want to produce large amounts of anti-CRISPR to increase the chance of inhibiting CRISPR immunity. But excessive production of anti-CRISPR prevents the phage from replicating and is ultimately toxic. That’s why control is important.

To achieve this control, phages have another protein in their toolbox: an anti-CRISPR-associated (or Aca) protein that often coexists with the anti-CRISPRs themselves.

Aca proteins act as regulators of phage counterdefense. They ensure that the initial burst of anti-CRISPR production that inactivates CRISPR is then quickly dampened to low levels. This way, the phage can allocate energy where it is needed most: its replication and ultimately its release from the cell.

We found that this regulation occurs at multiple levels. Before a protein can be produced, the gene sequence in DNA must first be transcribed into a messenger RNA. This is then decoded or translated into a protein.

Many regulatory proteins function by inhibiting the first step (transcription into messenger RNA), others inhibit the second (translation into protein). Either way, the regulator often acts as a kind of ‘roadblock’, binding to DNA or RNA.

Intriguingly and unexpectedly, the Aca protein we examined does both – even though its structure would suggest that it is merely a transcriptional regulator (a protein that regulates the conversion of DNA into RNA), similar to the proteins that have been used for decades. investigated.

We also investigated why this extra strict control at two levels is necessary. Once again, it seems to be all about the dosage of the anti-CRISPRs, especially since the phage replicates its DNA inside the bacterial cell. This replication will invariably lead to the production of messenger RNAs, even in the presence of transcriptional control.

Therefore, it appears that additional regulation is needed to control anti-CRISPR production. This goes back to the toxicity of the overproduction of this counter-defense protein, to the damage done when there is “too much of a good thing.”

Sophisticated operation

What does this research mean in the big picture? We now know much more about how anti-CRISPR implementation occurs. It requires sophisticated control for the phage to be successful in its fight against the host bacteria.

This is important in nature, but also when it comes to the use of phages as alternative antimicrobial agents.

Knowing every detail about something as obscure-sounding as anti-CRISPR-associated proteins could make the difference between the phage succeeding or succumbing – and between life or death, not only for the phage, but also for a person infected with antibiotic resistant bacteria. bacteria.

Nils BirkholzPostdoctoral researcher in Molecular Microbiology, University of Otago
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