The increasing prevalence of multidrug-resistant bacteria has intensified the search for alternative therapeutic strategies. Bacteriophages (the natural viral predators of bacteria) are one promising solution. However, bacterial immune systems confer phage resistance, which can limit the efficacy of phage therapies. Small-molecule modulators of bacterial immunity are a promising but underexplored strategy to enhance phage therapy. We report the first small-molecule inhibitors of the Pycsar immune system, a 3',5'-cCMP signal-based defense mechanism, in bacteria. These inhibitors exhibit efficacy in Escherichia coli cells, enabling phage Bas34 to overcome Pycsar-mediated resistance. The Pycsar system relies on two proteins: a CTP cyclase, which generates the cCMP signal, and a cCMP-activated transmembrane effector, which disrupts the bacterial membrane of the host cells and prevents phage reproduction. Our findings reveal that the identified inhibitors specifically target the cytotoxic effects of the transmembrane effector rather than the signal-producing cyclase. These molecules highlight the promise of chemical modulators to suppress bacterial immunity and, thereby, expand the therapeutic potential of bacteriophages against multidrug-resistant pathogens.
Addo et al. (Thu,) studied this question.