Project description:Bacteriophage genomes exhibit exceptional diversity in nucleobase modifications, which primarily function to counteract host immunity and reshape DNA physicochemical properties. Recent discoveries of aGPT-Pplase2-catalyzed novel thymidine hypermodifications reveal a broader enzymatic and chemical diversity in phage DNA modification systems. However, the diversity of thymidine hypermodification in other bacteriophages remains largely unexplored. Here we discovered a novel thymidine hypermodification, Na-dapT, in the Acinetobacter baumannii phage SH-Ab 15599, and elucidated its biosynthetic pathway, including the key diamine DNA transferase (DADT, formerly aGPT-Pplase2). DADT utilizes the abundant metabolite 1,3-diaminopropane of host to modify 5hmdU-DNA, exhibiting broad in vitro substrate specificity but a strong in vivo preference for 1,3-diaminopropane. Structural and mutagenesis analyses revealed the molecular basis for substrate recognition and catalysis. The Na-dapT modification occurs specifically at TG dinucleotides and confers resistance to multiple host restriction enzymes, enabling phage escape from the host restriction-modification system. Furthermore, RNA-seq analysis showed that phage infection reprograms host metabolism, upregulating genes for 1,3-diaminopropane synthesis to supply the modification precursor. Our study identified SH-Ab 15599 DADT as a versatile enzyme responsible for thymidine hypermodification, and comprehensively describes a viral strategy of exploiting host metabolites for DNA modification to evade bacterial defense.

2026-03-05 | GSE322957 | GEO

Acinetobacter phage Maestro

Project description:Acinetobacter phage Maestro Genome sequencing

| PRJNA658578 | ENA

Acinetobacter phage AJO1

Project description:Acinetobacter phage AJO1 Genome sequencing

| PRJNA353262 | ENA

Rational in vitro design of a two-phage cocktail against a contemporary Acinetobacter baumannii strain recovered from a burned patient at CHUV

Project description:Acinetobacter baumannii is currently a major threat to human health. With the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains, the development of complementary strategies is needed. A promising complimentary and realistic strategy could be phage therapy, which uses bacteriophages (phages), i.e viruses that specifically infect and kill bacterial cells during their life cycle. We designed a two-phage cocktail highly efficient against an extensive drug-resistant (XDR) A. baumannii isolate collected from a patient with burn wound infection at CHUV (termed Ab125). A first in vitro screen of our collection of 34 different phages identified only phage vB_AbaM_3098 as capable of lysing Ab125. However, quick selection of phage-resistant clones (termed Ab139) occurred. Comparative genomics and proteomics between Ab125 and Ab139 revealed several key variations. Very interestingly, we observed that Ab139 became susceptible to six different phages in the collection, otherwise inactive on Ab125. Phage-resistance was also selected when Ab139 was challenged with either of the six phages, with bacterial regrowth observed between 14 h and 16 h. However, combination of vB_AbaM_3098 and vB_AbaM_3014 led to a two-phage cocktail capable of totally inhibiting the growth of Ab125. Treatment with the phage cocktail led to 90% survival after 5 days in the in vivo Galleria Mellonella model of infectious diseases, compared to 0% in the non-treated group. We show that the combination of a phage that only slightly shifted the in vitro bacterial growth curve with an “inactive phage” led to the formulation of a highly bactericidal phage cocktail against Ab125. We then tested the therapeutic potential of the assembled cocktail in synergy with antibiotics and found a synergy with colistin. This work highlights the complexity sometimes involved in the assembly of potent phage cocktail.

2025-12-08 | PXD062593 | Pride

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