A conserved phage phosphoesterase enables evasion of bacterial antiviral immunity

With the increasing prevalence of drug-resistant bacteria, antimicrobial resistance emerges as a global public health threat. Mycobacteriophages show exciting prospects for the treatment of drug-resistant bacterial infections. However, the molecular mechanism through which they escape host bacterial defenses remains unclear. Here, we report that the gene gp48 of the mycobacteriophage A10ZJ24, which encodes a metallophosphoesterase-like protein, is essential for killing Mycobacterium tuberculosis. Gp48 is expressed during early stages of phage infection, and the Gp48 protein efficiently disrupts mycobacterial genomic DNA integrity, thereby silencing the expression of multiple anti-phage defense genes. While gp48-deletion phages infect and inject their DNA normally into M. tuberculosis cells, they are not able to impair the activation of the bacterial anti-phage genes which inhibit the replication of the genomic DNA of the mutant phage. This study thus identifies a phage metallophosphoesterase as a novel tool for subverting host bacterial antiviral immunity and killing M. tuberculosis. Our work fills a critical gap in the current knowledge on the arms race between mycobacteriophages and M. tuberculosis.