Multiplicity of type 6 secretion system toxins limits the evolution of resistance

• DOI: 10.1073/pnas.2416700122
• Publication Date: 2025-01-09T16:58:52Z
• Authors: William P. J. Smith; Ewan Armstrong-Bond; Katharine Z. Coyte; Christopher G. Kn...; Marek Basler; Michael A. Brockh...
• Keywords: Bacterial Toxins; microbiology; Evolutionary mechanisms; Type VI Secretion Systems/metabolism; Biological Sciences; Microbiology; Biological Evolution; secretion systems; combination therapy; Evolution, Molecular; Bacterial Toxins/metabolism; Escherichia coli/genetics; Acinetobacter/genetics; evolution; biotherapeutics; Bacterial Secretion Systems; bacterial toxins

The bacterial type 6 secretion system (T6SS) is a toxin-injecting nanoweapon that mediates competition in plant- and animal-associated microbial communities. Bacteria can evolve de novo resistance against T6SS attacks, but far from universal natural communities, suggesting key features of weaponry may act to limit its evolution. Here, we combine ecoevolutionary modeling experimental evolution examine how toxin multiplicity Acinetobacter baylyi attackers shape susceptible Escherichia coli competitors. In both our models experiments, find combinations multiple distinct toxins by creating genetic bottlenecks, driving resistant lineages extinct before they reach high frequency. We also show that, paradoxically, single-toxin drive the cross-resistance, protecting bacteria unfamiliar combinations, even though such evolutionary pathways were inaccessible multitoxin attackers. Our findings indicate comparable antimicrobial anticancer combination therapies, arsenals function competing microbes. This helps us understand why T6SSs remain widespread effective weapons many T6SS-armed encode functionally diverse anticompetitor toxins.