New discovery in the fight against harmful bacteria

16 Jul. () –

An unexpected discovery has led to significant progress in the fight against harmful bacteria. An international team of researchers, led by Professor Peter Fineran of the University of Otago (New Zealand), investigated a particular protein used by bacteria-infecting viruses, known as phages.

Research into this microscopic arms race between bacteria and phages is important because it may lead to alternatives to antibiotics. Published in Nature, the study analyzed a protein that phages use when deploying anti-CRISPR, their method for blocking the CRISPR–Cas immune system of bacteria.

Lead author Nils Birkholz, from Otago’s Department of Microbiology and Immunology, says understanding how phages interact with bacteria is an important step on the path to using phages against bacterial pathogens in human health or agriculture. “Specifically, we need to know about the defence mechanisms, such as CRISPR, that bacteria use to protect themselves against phage infection – similar to how we use our body’s immune system against viruses – and how phages can counteract these defences.

“For example, if we know how phages kill a specific bacteria, this helps to identify appropriate phages to use as antimicrobials. More specifically, it is important to understand how phages control their counter-defense arsenal, including anti-CRISPR, after an infection: we need to understand how phages regulate the expression of genes that are useful in their battle against bacteria,” he says.

The research also revealed how carefully phages must use their anti-CRISPRs. “We already knew that a particular phage protein has a part, or domain, that is very common in many proteins involved in gene regulation; this helix-turn-helix (HTH) domain is known to be able to specifically bind to DNA sequences and, depending on the context, can either turn a gene on or off. “What we have discovered is that the HTH domain of this protein is much more versatile and presents a mode of regulation that was previously unknown. It can use this domain not only to bind to DNA, but also to its RNA transcript, the molecule that acts as a mediator between the DNA sequence and the anti-CRISPR encoded in it. Since this protein is involved in regulating the production of an anti-CRISPR, it means that this regulation has additional layers: it occurs not only through the DNA binding mechanism, but also through the new mechanism we discovered of messenger RNA binding,” says the expert.

The researchers say the finding could have major implications for understanding gene regulation. “Deciphering this unexpectedly complex regulation is an important step forward in understanding how phages can evade CRISPR-Cas defenses and kill target bacteria in a variety of applications. The discovery is particularly exciting for the scientific community because it shows a new regulatory mechanism in a well-studied protein family.”

HTH domains have been extensively investigated since they were discovered in the early 1980s, so it was initially thought that this protein would act like any other protein with an HTH domain. “We were very surprised when we discovered this new mode of action. This finding has the potential to change the way the field views the function and mechanism of this critical and extended protein domain, and could have major implications for our understanding of gene regulation,” he concludes.