ADP-ribosyl-transferases (ARTs) are enzymes with various functions that are widespread in prokaryotes, eukaryotes, and viruses. Recent genome analyses reveal that many phages possess genes encoding ARTs. However, to date, only a few functions of ARTs (ModA, ModB, and Alt) from a single phage, the well-known Escherichia phage T4, are known. These enzymes NADylate or RNAylate host proteins involved in transcription and translation, thus participating in the reprogramming of the host cell. Here, we explore the role of the two ARTs, Alt1 and Alt2, of Shewanella phage Thanatos. Both proteins are present in the fully assembled phage and actively modify target proteins by NADylation immediately after phage infection. Purified proteins also show pronounced self-modification. In the absence of functional ARTs there is an influence on the phage fitness as the number of produced phage Thanatos progeny drops by a level of 10. We have identified some potential target proteins, which include proteins of the central metabolism and also several potential phage defense systems, such as toxin-antitoxin systems or a dNTPase. First results suggest that Thanatos ART activity may, in fact, interfere with the host defense. Moreover, Alt1 can partly restore the infectivity of the E. coli T5 phage when it is co-expressed with a dGTPase, an anti-phage defense strategy of bacteria. Therefore, we postulate that Alt1 and Alt2 represent the phage's first line of attack to disarm and prepare the host.