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Humans, and many other species, are host to diverse symbionts. It is often suggested that the mutual benefits of host-microbe relationships can alone explain cooperative evolution. Here, we evaluate this hypothesis with evolutionary modelling. Our model predicts that mutual benefits are insufficient to drive cooperation in systems like the human microbiome, because of competition between symbionts. However, cooperation can emerge if hosts can exert control over symbionts, so long as there are constraints that limit symbiont counter evolution. We test our model with genomic data of two bacterial traits monitored by animal immune systems. In both cases, bacteria have evolved as predicted under host control, tending to lose flagella and maintain butyrate production when host-associated. Moreover, an analysis of bacteria that retain flagella supports the evolution of host control, via toll-like receptor 5, which limits symbiont counter evolution. Our work puts host control mechanisms, including the immune system, at the centre of microbiome evolution. Humans, and many other species, carry a large set of beneficial microbes. Here, the authors present new theory and data to argue that these vital relationships only work when hosts can control their microbiome and suppress wayward symbionts.

Bacteria have evolved a diverse array of mechanisms to inhibit and kill competitors. However, why some bacteria carry such weapons while others do not remains poorly understood. Here we explore this question using the genomics of the bacteriocins of E. coli as a model system, which have large well-annotated bioinformatic resources. While bacteriocins occur widely, we find that carriage is particularly associated with pathogenic extra-intestinal (ExPEC) strains. These pathogens commonly carry large plasmids encoding bacteriocins alongside virulence factors and antimicrobial resistance mechanisms. Across all strains, we find many orphan immunity proteins, which protect against bacteriocins and suggest that these bacterial weapons are important in nature. We also present evidence that bacteriocin toxins readily move between strains via plasmid transfer and even between plasmids via transposons. Finally, we show that several E. coli bacteriocins are widely shared with the pathogen Salmonella enterica , further cementing the link to virulence. Our work suggests that the bacteriocins of E. coli are important antibacterial weapons for dangerous antimicrobial-resistant strains. Bacteria employ a range of competition systems that deliver toxins to inhibit competing strains. This study shows that these systems are particularly important for the ecology of virulent and antibiotic resistant bacteria.

Bacteria commonly use molecular weaponry to kill or inhibit competitors. Genes encoding many weapons and their associated immunity mechanisms can be transmitted horizontally. These transfer events are striking because they appear to undermine bacterial weapons when given to competing strains. Here, we develop an ecological model of bacterial warfare to understand the impacts of horizontal gene transfer. Our model predicts that weapon gene transfer from an attacker to a target strain is possible, but will typically occur at a low rate such that transfer has a negligible impact on competition outcomes. We tested the model empirically using a transmissible plasmid encoding colicin E2, a potent antibacterial toxin produced by Escherichia coli . As predicted by the model, we find that toxin plasmid transfer is feasible during warfare, but the resulting transconjugants remain rare. However, exploring the model further reveals realistic conditions where transfer is predicted to have major impacts. Specifically, the model predicts that whenever competing strains have access to unique nutrients, transconjugants can proliferate and reach high abundances. In support of these predictions, short- and long-term experiments show that transconjugants can thrive when nutrient competition is relaxed. Our work shows how horizontal gene transfer can reshape bacterial warfare in a way that benefits a weapon gene and strains that receive it. Interestingly, we also find that there is little cost to a strain that transfers a weapon gene, which is expected to further enable the horizontal gene transfer of molecular weapons.

Nuclease bacteriocins are potential antimicrobials for the treatment of antibiotic-resistant bacterial infections. While the mechanism of outer membrane translocation is beginning to be understood, the mechanism of inner membrane transport is not known. Bacteria exploit a variety of attack strategies to gain dominance within ecological niches. Prominent among these are contact-dependent inhibition (CDI), type VI secretion (T6SS), and bacteriocins. The cytotoxic endpoint of these systems is often the delivery of a nuclease to the cytosol. How such nucleases translocate across the cytoplasmic membrane of Gram-negative bacteria is unknown. Here, we identify a small, conserved, 15-kDa domain, which we refer to as the inner membrane translocation (IMT) domain, that is common to T6SS and bacteriocins and linked to nuclease effector domains. Through fluorescence microscopy assays using intact and spheroplasted cells, we demonstrate that the IMT domain of the Pseudomonas aeruginosa -specific bacteriocin pyocin G (PyoG) is required for import of the toxin nuclease domain to the cytoplasm. We also show that translocation of PyoG into the cytosol is dependent on inner membrane proteins FtsH, a AAA+ATPase/protease, and TonB1, the latter more typically associated with transport of bacteriocins across the outer membrane. Our study reveals that the IMT domain directs the cytotoxic nuclease of PyoG to cross the cytoplasmic membrane and, more broadly, has been adapted for the transport of other toxic nucleases delivered into Gram-negative bacteria by both contact-dependent and contact-independent means. IMPORTANCE Nuclease bacteriocins are potential antimicrobials for the treatment of antibiotic-resistant bacterial infections. While the mechanism of outer membrane translocation is beginning to be understood, the mechanism of inner membrane transport is not known. This study uses PyoG as a model nuclease bacteriocin and defines a conserved domain that is essential for inner membrane translocation and is widespread in other bacterial competition systems. Additionally, the presented data link two membrane proteins, FtsH and TonB1, with inner membrane translocation of PyoG. These findings point to the general importance of this domain to the cellular uptake mechanisms of nucleases delivered by otherwise diverse and distinct bacterial competition systems. The work is also of importance for the design of new protein antibiotics.

Bacteria exploit an arsenal of antimicrobial peptides and proteins to compete with each other. Three main competition systems have been described: type six secretion systems (T6SS); contact dependent inhibition (CDI); and bacteriocins. Unlike T6SS and CDI systems, bacteriocins do not require contact between bacteria but are diffusible toxins released into the environment. Identified almost a century ago, our understanding of bacteriocin distribution and prevalence in bacterial populations remains poor. In the case of protein bacteriocins, this is because of high levels of sequence diversity and difficulties in distinguishing their killing domains from those of other competition systems. Here, we develop a robust bioinformatics pipeline exploiting Hidden Markov Models for the identification of nuclease bacteriocins (NBs) in bacteria of which, to-date, only a handful are known. NBs are large (>60 kDa) toxins that target nucleic acids (DNA, tRNA or rRNA) in the cytoplasm of susceptible bacteria, usually closely related to the producing organism. We identified >3000 NB genes located on plasmids or on the chromosome from 53 bacterial species distributed across different ecological niches, including human, animals, plants, and the environment. A newly identified NB predicted to be specific for Pseudomonas aeruginosa (pyocin Sn) was produced and shown to kill P. aeruginosa thereby validating our pipeline. Intriguingly, while the genes encoding the machinery needed for NB translocation across the cell envelope are widespread in Gram-negative bacteria, NBs are found exclusively in γ-proteobacteria. Similarity network analysis demonstrated that NBs fall into eight groups each with a distinct arrangement of protein domains involved in import. The only structural feature conserved across all groups was a sequence motif critical for cell-killing that is generally not found in bacteriocins targeting the periplasm, implying a specific role in translocating the nuclease to the cytoplasm. Finally, we demonstrate a significant association between nuclease colicins, NBs specific for Escherichia coli, and virulence factors, suggesting NBs play a role in infection processes, most likely by enabling pathogens to outcompete commensal bacteria.

Redox-regulated effector systems that counteract oxidative stress are essential for all forms of life. Here we uncover a new paradigm for sensing oxidative stress centred on the hydrophobic core of a sensor protein. RsrA is an archetypal zinc-binding anti-sigma factor that responds to disulfide stress in the cytoplasm of Actinobacteria. We show that RsrA utilizes its hydrophobic core to bind the sigma factor σ R preventing its association with RNA polymerase, and that zinc plays a central role in maintaining this high-affinity complex. Oxidation of RsrA is limited by the rate of zinc release, which weakens the RsrA–σ R complex by accelerating its dissociation. The subsequent trigger disulfide, formed between specific combinations of RsrA’s three zinc-binding cysteines, precipitates structural collapse to a compact state where all σ R -binding residues are sequestered back into its hydrophobic core, releasing σ R to activate transcription of anti-oxidant genes. Counteracting oxidative stress is essential in all organisms. Here, the authors outline a mechanism used by actinomycete bacteria in which oxidation of zinc-binding RsrA blocks its interaction with σ R by sequestering hydrophobic residues used to bind σ R within its own core.

Abstract Salmonella enterica, a prominent enteric pathogen, employs sophisticated iron acquisition mechanisms to overcome host-imposed iron limitation, notably through the production and uptake of siderophores—small, high-affinity iron-chelating compounds that scavenge iron from the host environment. In this study, we investigate how environmental pH influences Salmonella’s preference for its endogenous siderophores versus exogenous siderophores within the physiological range of the gastrointestinal tract. Through competition assays, gene expression analysis, and siderophore quantification, we demonstrate that Salmonella increasingly relies on exogenous siderophores under acidic conditions. This shift is attributed to reduced production of its endogenous siderophores, enterobactin and salmochelin. Deletion of the sigma factor RpoS enhances iron acquisition through increased endogenous siderophore production at low pH, suggesting a role in iron homeostasis regulation. Our findings reveal a pH-dependent difference in Salmonella’s iron acquisition strategy, highlighting the pathogen’s versatility in nutrient acquisition across varying gastrointestinal conditions. This research provides insights into Salmonella’s pathogenicity and may inform the development of targeted interventions for Salmonella infections.

The data for the charts are taken from 572 farm in the SMS data base which have 1,064,703 mated females for the last 52 weeks with production at 23-plus pigs weaned/mated female/year. [...]you see there is a lot of variation in farrowing rate by farm (blue line). [...]a farm needs to work to get more weaned sows bred by day six. [...]female death loss percentage had moderate influence on pigs weaned/mated female/year, and retention percentage had very little effect.