Integration of chemical defense in the context of the bacterial immune system

Under the constant threat of predation by (bacterio-)phages, bacteria evolved a vast array of anti-phage defense mechanism. Besides protein- and RNA-based defense systems, recent studies have highlighted the role of Streptomyces-derived secondary metabolites, such as the DNA-intercalating anthracyclines1 as well as several aminoglycoside antibiotics as further facet of bacterial immunity2-3. Molecules of both classes have been shown to inhibit infection of various dsDNA phages by interfering with an early stage of the phage life cycle3.

Here, we focus on the influence of antibiotic resistance genes on the molecular versatility of aminoglycosides. Remarkably, we showed that drug modification via different acetyltransferases as well as target site modification via 16S rRNA methylation enables an uncoupling of the antibacterial and antiviral properties of these compounds, providing the prerequisite for community-wide antiphage defense. Inhibition of a Streptomyces phage was also achieved using the supernatants from natural aminoglycoside producers, hinting at a broad physiological significance of the antiviral properties of aminoglycosides.4

Additionally, we aim to assess specific phage characteristics that render them susceptible to chemical defense mechanisms. To this end, a diverse set of Streptomyces phages as well as the BASEL phage collection, comprising 69 fully characterized E. coli phages5, was screened against known antiphage small molecules. This screening revealed distinct, taxonomically-related clusters of phages, which are particularly sensitive to certain compounds. Moreover, we intend to explore the integration of chemical defense strategies within the broader context of the bacterial immunity by investigating potential synergistic interactions with other defense mechanisms.

We expect the outcomes of this project to deepen our understanding of multicellular defense via small molecules and provide a more comprehensive view of bacterial antiphage immunity.

1 Kronheim et al. (2018), Nature 564, 283-286, doi:10.1038/s41586-018-0767-x.

2 Kever et al. (2022), mBio 13, e00783-00722, doi:10.1128/mbio.00783-22.

3 Hardy et al. (2023), Trends Microbiol 31, 92-106, doi:10.1016/j.tim.2022.08.001.

4 Kever et al. (2024), µLife 5, uqae015, doi: 10.1093/femsml/uqae015.

5 Maffei et al. (2021), PLoS Biol 19, e3001424, doi:10.1371/journal.pbio.3001424