Bacteriophage-project
Bacteria deploy diverse antiphage defense systems, including small bioactive molecules providing protection at the multicellular level. DNA-intercalating anthracyclines such as daunorubicin exhibit broad antiphage activity, but the underlying mechanism had remained elusive. Here, we systematically screened the Escherichia coli BASEL phage collection to elucidate the mode of action of daunorubicin. We identified taxonomically distinct clusters of susceptible viral groups and demonstrate that daunorubicin blocks infection of T5-like phages (Markadamsvirinae) after first-step transfer (FST) as revealed by long-read sequencing. Continued expression of pre-early genes leads to abortive infection via 'mutual destruction', where both phage and host succumb. Analogous phenotypes of abortive infection were observed for taxonomically diverse phages with different DNA-intercalating antiphage molecules. Notably, we show that daunorubicin synergizes with downstream nucleic acid-targeting defences underscoring context dependency in the observed defense phenotype. Our findings reveal how chemical defense contributes to the multilayered antiviral immunity and highlight the intricate interplay between mechanistic inhibition and infection outcome.