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Chemical inhibitor of cell wall alanylation sensitizes bacteria to diverse bacteriophages, revealing the widespread immunity conferred by cell wall modification. 

This review comprehensively reports historical and recent examples of natural products that either prevent bacteriophages from infecting bacteria, promote those infections, or regulate the induction of the lytic cycle of prophages. 

Abstract The rise of antibiotic resistance motivates a revived interest in phage therapy. However, bacteria possess dozens of anti-bacteriophage immune systems that confer resistance to therapeutic phages. Chemical inhibitors of these anti-phage immune systems could be employed as adjuvants to overcome resistance in phage-based therapies. Here, we report that anti-phage systems can be selectively inhibited by small molecules, thereby sensitizing phage-resistant bacteria to phages. We discovered a class of chemical inhibitors that inhibit the type II Thoeris anti-phage immune system. These inhibitors block the biosynthesis of a histidine-ADPR intracellular ‘alarm’ signal by ThsB and prevent ThsA from arresting phage replication. These inhibitors promiscuously inhibit type II Thoeris systems from diverse bacteria—including antibiotic-resistant pathogens. Chemical inhibition of the Thoeris defense improved the efficacy of a model phage therapy against a phage-resistant strain ofP. aeruginosain a mouse infection, suggesting a therapeutic potential. Furthermore, these inhibitors may be employed as chemical tools to dissect the importance of the Thoeris system for phage defense in natural microbial communities. 

Abstract To overtake competitors, microbes produce and secrete secondary metabolites that kill neighboring cells and sequester nutrients. This natural product-mediated competition likely evolved in complex microbial communities that included viral pathogens. From this ecological context, we hypothesized that microbes secrete metabolites that “weaponize” natural pathogens (i.e., bacteriophages) to lyse their competitors. Indeed, we discovered a bacterial secondary metabolite that sensitizes other bacteria to phage infection. We found that this metabolite provides the producer (aStreptomycessp.) with a fitness advantage over its competitor (Bacillus subtilis) by promoting phage infection. The phage-promoting metabolite, coelichelin, sensitizedB. subtilisto a wide panel of lytic phages, and it did so by preventing the early stages of sporulation through iron sequestration. Beyond coelichelin, other natural products may provide phage-mediated competitive advantages to their producers—either by inhibiting sporulation or through yet-unknown mechanisms.