Bacteria Use Natural Products to Expose Competitors to Viruses, Opening New Pathways for Antimicrobial Strategies

A recent study In Nature reveals that bacteria can use natural products to make nearby competitors more susceptible to viral infection, adding a new layer to our understanding of microbial competition. Microbes compete for resources by secreting secondary metabolites that can kill rival bacteria and secure nutrients. The study suggests that these metabolites might also make competitors more vulnerable to bacteriophages, viruses that infect bacteria.

Researchers identified coelichelin, a secondary metabolite produced by Streptomyces bacteria, which sensitized Bacillus subtilis to phage infection. Coelichelin, a siderophore, binds iron, which in turn prevents B. subtilis from activating Spo0A, a regulator involved in the stationary phase and sporulation. This disruption made B. subtilis more susceptible to infection by several phages, including SPO1, SP10, SP50, and Goe2.

Metabolomics analysis also indicated that other bacterial metabolites might provide similar advantages by affecting phage sensitivity. The study highlights a previously unexplored interaction between bacterial natural products and viruses, showing how one microbe’s secretion can alter the outcome of competition by increasing its competitor’s vulnerability to phages.

To better understand the implications of these findings, we conducted an email interview with investigator Joseph Gerdt, PhD assistant professor of chemistry at Indiana University, about coelichelin’s potential therapeutic applications. Gerdt explained that the interaction between coelichelin and phages could have significant effects on microbial communities in environments like the human gut or soil. He said, "We hypothesize that coelichelin (and other molecules that help phages infect certain bacteria) are likely to promote the phage-induced lysis of those bacteria that are sensitized by the molecule. This would shape microbial communities (like gut or soil) by decreasing the numbers of those bacterial species and allowing other bacteria (or fungi) to proliferate more."

He highlights that microbes likely produce molecules like coelichelin naturally, shaping their environments without any external intervention. "It’s exciting to us that a natural product (coelichelin) has this effect. Because this means that microbes are likely already making molecules that are doing this. In other words, we don’t have to add coelichelin to the soil or to a microbiome to observe this effect. It is probably already shaping these communities and we didn’t know it."

Although, he also clarifies that Bacillus subtilis, used in their study, is not part of the human microbiome, so they do not yet have evidence of coelichelin promoting phage infection in human microbes. "Bacillus subtilis is not a member of the human microbiome, so we do not yet have evidence of coelichelin promoting phage infection of any human symbionts. However, clostridia are present in humans, and these also have Spo0A-regulated dormancy. So a similar mechanism may apply—but we have not tested that."

Gerdt also adds an important note about phage types: "We only tested lytic phages. Many phages can be lysogens, so coelichelin and similar molecules that promote infection could also promote the spread of lysogenic phages and the numerous genes they carry that can even benefit their hosts."

Gerdt is optimistic about coelichelin’s potential in enhancing phage therapy, especially for antibiotic-resistant infections. "Assuming that coelichelin ends up helping phages infect a pathogen (like a clostridium, for example), then certainly we think it could help phage therapy be more effective in vivo." He further explains that the underlying mechanism—iron sequestration—could be used with other iron chelators that are already clinically available. "Since the basic mechanism is sequestering iron, any iron chelator could even be used. Several iron chelators have been clinically used to treat iron overload, so many options exist, and some may have a smoother path to therapeutic use."

Although, he points out some challenges and nuances in this approach. "One challenge to note is that we believe some bacteria will actually respond in the opposite way to iron chelation (i.e., they will become MORE resistant to phage infection). We saw this to be true with Vibrio cholerae phages. So, any bacteria-phage combination should be tested in vitro first."

Gerdt emphasized the importance of careful testing, particularly in animal models, before applying these strategies in clinical settings. "First we need to find the pathogens or human symbionts that are sensitized to phages by coelichelin or another molecule. I don’t know if coelichelin will get us there." He notes that his team is already investigating other molecules with similar potential. "However, in unpublished work we have already found that another molecule promotes phage infection in some human pathogens via a different mechanism. We are currently running animal infection models, and we will see how promising they are (both in helping the phage kill bacteria, and in the molecules not being toxic to the animals)."

Gerdt also acknowledges the ethical considerations in applying such treatments, especially in clinical settings. "I do not run any clinical trials or work with humans, so my knowledge of the ethics there is limited." He underscores that, like other phage therapies, this approach would likely be used as a "last-resort" option for difficult infections. "For treatments of nasty infections, these efforts would certainly be a ‘last-resort’ treatment after all proven antibiotics have failed (this is the case with other phage therapies as far as I know, like work by Paul Turner at Yale, for example)."

These findings suggest that microbial competition is influenced not only by direct interactions but also by the interplay between natural products and viral infection. The discovery may offer new approaches for understanding microbial dynamics and developing antimicrobial strategies.

Reference

Zang, Z., Zhang, C., Park, K.J. et al. Streptomyces secretes a siderophore that sensitizes competitor bacteria to phage infection. Nat Microbiol (2025). https://doi.org/10.1038/s41564-024-01910-8