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NAD to the bone: How bacteria put phages under aRES-t … and how phages fight back

Danny P Williams-Jones1, Jack P K Bravo1

  • 1Institute of Science and Technology Austria, Klosterneuburg, Austria.

Cell Host & Microbe
|June 10, 2026
PubMed

Insights

Researchers discovered aRES, a novel bacterial immune protein family that depletes NAD+, hindering phage replication. Phages evolved countermeasures to overcome this defense mechanism.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Immunology

Background:

  • Bacterial infections are a growing threat due to antibiotic resistance.
  • Phages are viruses that infect bacteria and are a potential alternative to antibiotics.
  • Bacterial immune systems are crucial for defense against phages.

Purpose of the Study:

  • To discover and characterize novel bacterial immune proteins.
  • To understand the mechanism of action of these proteins against phages.
  • To investigate phage counter-evolutionary strategies.

Main Methods:

  • Protein identification and characterization.
  • Enzyme activity assays to measure NAD+ depletion.
  • Phage infection assays to assess aRES efficacy.
  • Bioinformatic analysis of phage genomes for resistance mechanisms.

Main Results:

  • Discovery of aRES, a new family of bacterial immune proteins.
  • aRES depletes cellular NAD+ (nicotinamide adenine dinucleotide), producing unusable cleavage products.
  • Identification of an invader-specific trigger for aRES activation.
  • Characterization of two distinct phage countermeasures against aRES.

Conclusions:

  • aRES represents a novel bacterial defense mechanism against phages by targeting NAD+ metabolism.
  • Phages have evolved specific strategies to evade aRES, highlighting an ongoing evolutionary arms race.
  • Understanding this interaction could inform the development of new phage-based therapies.

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