Despite the advancement in medical science, bacteria have obtained resistance against the antibiotics used to treat them, resulting in the ineffectiveness of traditional antibiotics. However, recent research has revealed that certain specific viruses could fight these antibiotic-resistant bacteria, offering a solution.

According to the study, viruses known as bacteriophages, or phages, can fight the bacteria without infecting humans or other higher organisms. Researchers explained that Phages inject their DNA into the bacterial cell, multiply to large numbers using the resources of the host, and then burst out to infect more antibiotic-resistant bacteria in the vicinity.

These viruses are naturally occurring antibiotics used centuries ago, but following the drug and medical advancements their effectiveness was ignored. Now, when modern pharma fails, this forgotten remedy is relevant.

"Our new research looked at one particular protein used by phages to bypass the natural defences of antibiotic-resistant bacteria. We found this protein has an essential control function by binding to DNA and RNA. This increased understanding is an important step towards using phages against bacterial pathogens in human health or agriculture." Referring to a report by The Conservation.

CRISPR defence system

As per the report, there are hurdles to using phages to target antibiotic-resistant bacteria. Resembling how our bodies have an immune mechanism against viruses, the bacteria also develop defences against phage infections.

antibiotic-resistant bacteria
Image Source: Lysol

“Clustered regularly interspaced short palindromic repeats”, or CRISPR is one such defence. CRISPR systems behave like “molecular scissors” which cut down DNA into pieces, both in a lab setting or in nature, inside a bacterium. through this process, it kills the phage.

The antibiotic-resistant bacteria's CRISPR defence system is the only barrier that will allow antibiotic-resistant bacterial infection to survive against phage. The researchers are investigating "so-called anti-CRISPRs: proteins or other molecules that phages use to inhibit CRISPR."

A bacteria with CRISPR defence can fight the phage. Therefore, it is important to inhabit the phase with a suitable anti-CRISPR that can neutralise the defence mechanism of the bacteria and kill it.

Anti-CRISPRs

According to the research, when phages face a powerful CRISPR defence, they automatically produce large amounts of anti-CRISPR to increase the chance of inhibiting CRISPR immunity.

However, its excessive production can prevent replication of the phage and is ultimately toxic, which needs to be controlled. This can be achieved through another protein present in the phage itself: an anti-CRISPR-associated (or Aca) protein that frequently occurs alongside the anti-CRISPRs themselves.

Aca proteins act as regulators of the phage's counter-defence. They make sure the initial burst of anti-CRISPR production that inactivates CRISPR is then rapidly dampened to low levels. That way, the phage can allocate energy to where it is most needed: its replication and, eventually, release from the cell. The Conservation report explains.

They found this regulation at multiple levels. "For any protein to be produced, the gene sequence in the DNA first needs to be transcribed into a messenger–RNA. This is then decoded, or translated, into a protein."

Most of the regulatory proteins function by inhibiting the first step (transcription into messenger-RNA), and some others inhibit the second (translation into protein). Either way, the regulator often acts as a “roadblock” of sorts, binding to DNA or RNA.

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

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

Therefore, it appears additional regulation is required to reign in anti-CRISPR production. This comes back to the toxicity of excessive production of this counter-defence protein, to the harm done when there's “too much of a good thing”.

Fine-tuned control

The research as a whole defines a lot more about how anti-CRISPR deployment occurs. It requires fine-tuned control to enable the phage to be successful in its battle against the host bacterium. The Conservation reported

The research has tested multiple possibilities regarding the effectiveness of phage to treat antibiotic-resistant bacteria. Getting to know every detail might disclose the possibilities of the phage succeeding or failing not just for itself but for those infected with antibiotic-resistant bacteria.

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