Biology subjects

Ingmer, H.

Publications and source records attributed to Ingmer, H..

16 recordsLinked to original sources

bioRxiv2026

Human airway model reveals host-pathogen co-infection dynamics of Staphylococcus aureus and Pseudomonas aeruginosa

Polymicrobial airway infections, particularly those involving Staphylococcus aureus and Pseudomonas aeruginosa, are a hallmark of severe chronic respiratory diseases such as those in people with cystic fibrosis (pwCF). Yet, the mechanisms enabling their co-existence remain poorly understood. Using a human air-liquid interface (ALI) airway model, we dissected host-pathogen and interspecies dynamics during mono- and co-infections with clinically relevant bacterial pathogens. We found that S. aureus strains exhibited distinct colonization patterns and virulence profiles, with the deletion of the agr quorum sensing locus leading to attenuated epithelial disruption. Additionally, the H1 component of P. aeruginosas type VI secretion system was critical for competitive exclusion of S. aureus, its deletion allowing for occasional co-localization of both species. Importantly, co-infection timing strongly influenced pathogen dominance and epithelial damage, with pre-colonization of ALI models with S. aureus prior to P. aeruginosa infection, mimicking clinical observations in CF. Our results reveal that strain-specific traits and secretion systems influence microbial competition and persistence in the airway and underscore the importance of physiologically relevant models for studying chronic infections. Moreover, they provide the foundation for exploring therapeutic strategies for polymicrobial infections that account for the colonization sequence and microbial evolution for treatment design.

microbiology↗

bioRxiv2025

Inhibition of agr Quorum Sensing in Staphylococci by Novel Thiazole-Indole Hybrid Compounds

The rise of multidrug-resistant Staphylococcus aureus has prompted the search for innovative, non-bactericidal therapeutic strategies. Anti-virulence approaches targeting quorum sensing (QS) pathways offer a promising alternative by disarming pathogenicity, potentially without exerting selective pressure for resistance. In this study, we report the identification of two novel thiazole-indole hybrid compounds, namely 2-[(6-methoxy-1H-indol-2-yl)methyl]-5-cyano-1,3-thiazol-3-amine (designated C3) and 3-amino-5-cyano-2-(5-chloro-1H-indol-2-yl) thiazole (designated C4), as potent inhibitors of the S. aureus accessory gene regulator (agr) quorum sensing system. Building on two heterocyclic scaffolds commonly used in medicinal chemistry and associated with QS modulation, these synthetic small molecules act on the S. aureus AgrC QS receptor, attenuating virulence without affecting bacterial viability. Both compounds significantly reduced the production of secreted virulence factors without promoting biofilm formation, a known drawback of some other QS inhibitors. Furthermore, their activity extended to Staphylococcus lugdunensis, while sparing the commensal Staphylococcus epidermidis, indicating pathogen-selective QS interference. These findings establish novel thiazole-indole hybrids as a promising chemotype for anti-virulence intervention and provide valuable chemical tools for probing agr-mediated regulation in Staphylococcus species.

microbiology↗

bioRxiv2025

Phage resistance impacts antibiotic susceptibility and virulence in Staphylococcus aureus

As antibiotic resistance continues to rise worldwide, phage therapy offers a promising solution by harnessing viruses that infect and kill bacteria. However, phage-resistance may develop, compromising therapy. Phage-resistance has primarily been linked to changes in major phage receptors that for the human pathogen Staphylococcus aureus are the cell-wall linked wall teichoic acids (WTA). To identify additional factors contributing to phage-resistance, S. aureus was evolved under selective pressure from lytic phages, including candidates from therapeutic phage cocktails, to obtain resistant clones. A third of the phage-resistant clones acquired mutations associated with cell-wall changes previously linked with phage resistance, namely in femA, involved in peptidoglycan crossbridge formation, and tagO, encoding the initiator of the WTA biosynthesis. The remaining clones had mutations in pathways not previously associated with phage-resistance, including nucleoside catabolism (deoC1), polyamine import (potAB) and DNA/RNA replication (cshA, ligA), suggesting that phage-resistance may be associated with phage-driven host takeover. Antibiotic susceptibility and virulence were diversely affected by the mutations; mutations in tagO increased {beta}-lactams sensitivity and attenuated virulence, whereas mutations in femA/ligA or cshA increased staphylococcal virulence in Galleria mellonella. This work demonstrates the involvement of several novel bacterial pathways in phage resistance, highlighting the complexity behind phage-bacterial interactions.

microbiology↗

bioRxiv2025

Mapping of Quorum Sensing Landscape of Commensal and Pathogenic Staphylococci Reveals a Largely Inhibitory Interaction Network

Staphylococci utilize secreted autoinducing peptides (AIPs) to regulate group behaviour through a process called quorum sensing (QS). For staphylococcal pathogens such as S. aureus, QS regulates expression of major virulence factors and QS inhibition has been proposed as an alternative to antibiotics for treatment of infections with methicillin resistant S. aureus (MRSA). Here, we surveyed the interaction map between QS systems of the pathogens Staphylococcus aureus, Staphylococcus epidermidis, and Staphylococcus lugdunensis and the 36 currently known AIPs from 22 staphylococcal species. We identified seven of these ribosomally synthesized and post-translationally modified peptides (RiPPs) in this study and all synthetic peptides were assessed for their ability to modulate QS. The mapped interactions of >280 native QS pairings were divided into human- and animal-associated staphylococci showing substantial differences in inhibitory potencies between the groups. In particular, AIPs of the bovine-associated species S. simulans displayed potential as QS inhibitors in the strains investigated in this study and were therefore chosen as starting point for a structure-activity relationship study. This study provides insights into the requirements for QS interference, yielding the most potent inhibitors reported to date for S. epidermidis and S. lugdunensis. Further, we tested an S. simulans AIP as anti-virulence agent in an assay to assess risk of acquired suppression of the inhibitory effect, and we established an assay set-up to successfully monitor agr deactivation of virulent MRSA by the QS inhibitor. Finally, a peptide was shown to attenuate skin infection caused by MRSA in a mouse model. Our results reveal a complex network of staphylococcal interactions and provide further impetus for the development of therapeutic strategies, based on QS modulation to target antibiotic-resistant pathogens. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/635662v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@f2be0aorg.highwire.dtl.DTLVardef@9aa0c2org.highwire.dtl.DTLVardef@1b02c26org.highwire.dtl.DTLVardef@12273a7_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2024

The two-component system ArlRS is essential for wall teichoic acid glycoswitching in Staphylococcus aureus

Staphylococcus aureus is among the leading causes of hospital-acquired infections. Critical to S. aureus biology and pathogenesis are the cell wall-anchored glycopolymers wall teichoic acids (WTA). Approximately one-third of S. aureus isolates decorates WTA with a mixture of 1,4- and {beta}1,4-N-acetylglucosamine (GlcNAc), which requires the dedicated glycosyltransferases TarM and TarS, respectively. Environmental conditions, such as high salt concentrations, affect the abundance and ratio of 1,4- and {beta}1,4-GlcNAc WTA decorations, thereby impacting biological properties such as antibody binding and phage infection. To identify regulatory mechanisms underlying WTA glycoswitching, we screened 1,920 S. aureus mutants (Nebraska Transposon Mutant Library) by immunoblotting for differential expression of WTA-linked 1,4- or {beta}1,4-GlcNAc using specific monoclonal antibody Fab fragments. Three two-component systems (TCS), GraRS, ArlRS, and AgrCA, were among the 230 potential hits. Using isogenic TCS mutants, we demonstrated that ArlRS is essential for WTA {beta}1,4-GlcNAc decoration through regulation of tarM but not tarS. ArlRS regulated tarM expression through the transcriptional regulator MgrA, which was responsive to Mg2+, but not Na+. Importantly, ArlRS-mediated regulation of WTA glycosylation affected S. aureus interaction with the innate receptor langerin and lysis by {beta}1,4-GlcNAc-dependent phages. Since WTA represents a promising target for future immune-based treatments and vaccines, our findings provide important insight to align targeting strategies with the S. aureus WTA glycosylation patterns during infection. ImportanceStaphylococcus aureus is a common colonizer of mucosal surfaces, but is also a frequent cause of severe infections in humans. Development of antibiotic resistance complicates treatment of S. aureus infections, increasing the need for antibiotic alternatives such as vaccines and therapies with bacterial viruses also known as phages. Wall teichoic acids (WTA) are abundantly-expressed glycosylated structures of the S. aureus cell wall that have gained attention as a promising target for new treatments. Importantly, WTA glycosylation patterns show variation depending on environmental conditions, thereby impacting phage binding and interaction with host factors, such as antibodies and innate pattern-recognition receptors. Here, we show that the two-component system ArlRS through its effector MgrA is involved in regulation of WTA glycosylation by responding to environmental changes in Mg2+ concentration. These findings may support the design of new treatment strategies that target WTA glycosylation patterns of S. aureus during infection.

microbiology↗

bioRxiv2023

Development of Stabilized Peptide Analogues to Study a Short-lived Peptide Signal that Regulates Cell-to-Cell Communication in Listeria monocytogenes

Quorum sensing (QS) is a mechanism that regulates group behavior in bacteria, and in Gram-positive bacteria, the communication molecules are often cyclic peptides, called autoinducing peptides (AIPs). We recently showed that pentameric thiolactone-containing AIPs from Listeria monocytogenes, and from other species, spontaneously undergo rapid rearrangement to homodetic cyclopeptides, which hampers our ability to study the activity of these short-lived compounds. Here, we developed chemically modified analogues that closely mimic the native AIPs while remaining structurally intact, by introducing N-methylation or thioester-to-thioether substitutions. The stablilized AIP analogues exhibit strong QS agonism in L. monocytogenes and allow structure-activity relationships to be studied. Our data provide evidence that loudly suggest that the most potent AIP is in fact the very short-lived thiolactone-containing pentamer. Further, we find that the QS system in L. monocytogenes is more promiscuous with respect to the structural diversity allowed for agonistic AIPs than reported for the more extensively studied QS systems in Staphylococcus aureus and Staphylococcus epidermidis. The developed compounds will be important for uncovering the biology of L. monocytogenes, and the design principles should be broadly applicable to the study of AIPs in other species.

microbiology↗

bioRxiv2023

Cross-species communication via agr controls phage susceptibility in Staphylococcus aureus

Bacteria and their viruses (phages) use quorum sensing (QS) systems to coordinate group behavior. In Staphylococcus aureus, QS plays a critical role in the transition from colonization to infection and involves the accumulation of auto-inducing peptides (AIPs). Humans and animals are also colonized by non-aureus staphylococci (NAS) that produce AIPs, many of which inhibit S. aureus QS. We found that QS induction is necessary for S. aureus susceptibility to the lytic phage, Stab20 and that in mixed communities with NAS producing inhibitory AIPs, S. aureus is protected from phage infection. The primary phage receptors in S. aureus are wall teichoic acids (WTA) substituted with - and/or {beta}-linked N- acetylglucosamine (GlcNAc). We show that QS induction reduces -GlcNAc substitutions and enables Stab20 infection through binding to {beta}-glycosylated WTA. However, in the presence of inhibitory AIPs or during co-culture with NAS, QS induction and Stab20 infection are impeded. Our results highlight how cross-species communication can significantly impact bacterial susceptibility to phages and may explain occasional failures observed when phages are used as antimicrobials in for example phage therapy.

microbiology↗

bioRxiv2023

Endogenous Staphylococcus aureus CRISPR-cas system limits phage proliferation and efficiently excises from the genome as part of the SCCmec cassette

CRISPR-Cas is an adaptive immune system that allows bacteria to inactivate mobile genetic elements. Approximately 50% of bacteria harbor CRISPR-cas, however in the human pathogen Staphylococcus aureus, CRISPR-cas loci are less common and often studied in heterologous systems. We analyzed the prevalence of CRISPR-cas in genomes of methicillin resistant Staphylococcus aureus (MRSA) isolated in Denmark. Only 2.9 % of the strains carried CRISPR-cas systems, but for strains of sequence type ST630 over half were positive. All CRISPR-cas loci were type III-A and located within the staphylococcal chromosomal cassette (SCCmec) type V(5C2&5) conferring {beta}-lactam resistance. Curiously, only 23 different CRISPR spacers were identified in 69 CRISPR-positive strains and almost identical SCCmec cassettes, CRISPR arrays and cas genes, are present in staphylococcal species other than aureus, suggesting that these were transferred horizontally. For the ST630 strain 110900, we demonstrate that the SCCmec cassette containing CRISPR-cas excises from the chromosome at high frequency. However, the cassette was not transferable under the conditions investigated. One of the CRISPR spacers targets a late gene in the lytic bacteriophage (phage) virus philPLA-RODI, and we show that the system protects against phage infection by reducing phage burst size. However, CRISPR-Cas can be overloaded or bypassed by CRISPR escape mutants. Our results imply that the endogenous type III-A CRISPR-Cas system in S. aureus is active against targeted phages, albeit with low efficacy. This suggests native S. aureus CRISPR-Cas offers only partial immunity, and in nature may work in tandem with other defense systems. ImportanceCRISPR-Cas is an adaptive immune system enabling bacteria and archaea to protect themselves against mobile genetic elements such as phages. In strains of Staphylococcus aureus, CRISPR-cas is rare, but when present, it is located within the SCCmec element encoding resistance to methicillin and other {beta}-lactam antibiotics. We show that the entire module is excisable, with almost identical versions found in different species of non-aureus staphylococci suggesting that the system only rarely acquires new spacers in S. aureus. Additionally, we show that in its endogenous form, the S. aureus CRISPR-Cas is active but inefficient against lytic phages, with phages being able to form escape mutants or overload the system. This leads us to propose that CRISPR-Cas in S. aureus offers only partial immunity in native systems, and so may work together with other defense systems to prevent phage-mediated killing.

microbiology↗

bioRxiv2023

Polyether ionophore antibiotics target drug-resistant clinical isolates, persister cells, and biofilms

Polyether ionophores are complex natural products known to transport various cations across biological membranes. While several members of this family are used in agriculture, e.g. as anti-coccidiostats, and have potent antibacterial activity, they are not currently pursued as antibiotics for human use. Polyether ionophores are typically grouped as having similar functions, despite the fact that they differ significantly in structure, and for this reason, it remains unclear how structure and activity are related. To triage whether certain members of the family constitute particularly interesting springboards for in-depth investigations, and future synthetic optimization, we here conduct a systematic comparative study of nine different polyether ionophores for their potential as antibiotics. This includes clinical isolates from bloodstream infections and studies of the compounds effects on bacterial biofilms and persister cells. We uncover distinct differences within the compound class and identify the compounds lasalocid, calcimycin, and nanchangmycin as having particularly interesting activity profiles for further development.

microbiology↗

bioRxiv2023

Quorum sensing inhibits Type III-A CRISPR-Cas system activity through repressing positive regulators SarA and ArcR in Staphylococcus aureus

CRISPR-Cas is an adaptive immune system that protects prokaryotes from the invasion of foreign genetic elements. The components and immunity mechanisms of CRISPR-Cas have been extensively studied, but the regulation of this system in Staphylococci remains unclear. Here, we show that in the S. aureus Type III-A CRISPR-Cas system, the Pcas of 300 bp located in cas1 displays as a critical regulatory node that initiates the transcription of cas gene clusters. We discovered two transcriptional regulators, SarA and CRP-like ArcR, promote the expression and activity of the CRISPR-Cas system by directly binding to the novel promoter Pcas. Furthermore, we demonstrated that the cell-cell communication, known as quorum sensing (QS), inhibits the activity of CRISPR-Cas system by repressing the positive regulators SarA and ArcR. Bioinformatic analyses suggest that Pcas is conserved in many Type II and III CRISPR-Cas systems in Firmicutes. Our data reveal a new regulatory mechanism for QS-mediated repression of the Type III-A CRISPR-Cas system, which may allow S. aureus to acquire foreign genetic elements encoding antibiotic resistance or virulence factors specifically at high cell density.

microbiology↗

bioRxiv2021

Bacteriophages encoding human immune evasion factors adapt to livestock-associated MRSA through rounds of integration and excision

In recent years there has been an increase in human infections with methicillin-resistant Staphylococcus aureus (MRSA) originating from livestock and strains carrying bacterial viruses of the Sa3int-family have disseminated into the community. Sa3int phages express immune evasion factors and are common in human staphylococcal strains. As the bacterial attachment site (attB) for Sa3int phages is mutated in livestock-associated strains, the integration frequency is low and a key question is how the phages are established. Here we show that Sa3int phages adapt to alternative bacterial integration sites by mutating the phage attachment sequence, attP, leading to enhanced integration at these sites. Using a model strain carrying the mutated attBLA of livestock-associated strains we find that once established, the Sa3int phage, {Phi}13 is inducible with release of heterogenous phage populations carrying mutations in attP that in part increase homology to alternative integration sites or attBLA. Compared to the original phage, the adaptive mutations increase phage integration in new rounds of infection. Also, Sa3int phages induced from livestock-associated outbreak strains reveal mutated attP sequences. We suspect that promiscuity of the phage-encoded recombinase allows this adaptation and propose it may explain how phages mediate "host jumps" that are regularly observed for staphylococcal lineages.

microbiology↗

bioRxiv2021

Chemical phylogenetics of the staphylococcal quorum sensing landscape

Staphylococci utilize secreted autoinducing peptides (AIPs) to regulate group behaviour through a process called quorum sensing (QS). Here, we survey the QS interaction landscape within the Staphylococcus genus by assembling a unique compound collection, comprising all the currently known AIPs. These ribosomally synthesized and posttranslationally modified peptides (RiPPs) were obtained by chemical synthesis and mapping of their ability to modulate QS was evaluated using reporter strains of common human and animal colonizing pathogens (S. aureus, S. epidermidis, S. lugdunensis). The resulting map of >200 native QS interactions provides a holistic view of nodes that contribute to the complex signalling network within the Staphylococcus genus. This overview reveals surprising cross-species QS induction and identify the first pan-inhibitory AIP, which is then shown to attenuate MRSA induced skin infection in a mouse model. Our results expose a complex universe of possible staphylococcal interactions and provide further impetus for development of therapeutics based on QS modulators targeting antibiotic resistant pathogens.

microbiology↗

bioRxiv2020

Screening for highly transduced genes in Staphylococcus aureus reveals both lateral and specialized transduction

Bacteriophage-mediated transduction of bacterial DNA is a major route of horizontal gene transfer in the human pathogen, Staphylococcus aureus. Transduction involves packaging of bacterial DNA by viruses and enables transmission of virulence and resistance genes between cells. To learn more about transduction in S. aureus, we searched a transposon mutant library for genes and mutations that enhanced transfer mediated by the temperate phage, {varphi}11. Using a novel screening strategy, we performed multiple rounds of transduction of transposon mutant pools selecting for an antibiotic resistance marker within the transposon element. When determining the locations of transferred mutations, we found that, within each pool of 96 mutants the screen had selected for just 1 or 2 transposon mutant(s). Subsequent analysis showed that the position of the transposon, rather than inactivation of bacterial genes, was responsible for the phenotype. Interestingly, from multiple rounds we identified a pattern of transduction that encompassed mobile genetic elements, as well as chromosomal regions both upstream and downstream of the phage integration site. The latter was confirmed by DNA sequencing of purified phage lysates. Importantly, transduction frequencies were lower for phage lysates obtained by phage infection rather than induction. Our results confirm previous reports of lateral transduction of bacterial DNA downstream of the integrated phage, but also indicate specialized transduction of DNA upstream of the phage, likely involving imprecise excision of the phage from the bacterial genome. These findings illustrate the complexity of transduction processes and increase our understanding of the mechanisms by which phages transfer bacterial DNA. ImportanceHorizontal transfer of DNA between bacterial cells contributes to the spread of virulence and antibiotic resistance genes in human pathogens. For Staphylococcus aureus, bacterial viruses are particularly important. These viruses, termed bacteriophages, can transfer bacterial DNA between cells by a process known as transduction, which despite of its importance is only poorly characterized. Here, we employed a transposon mutant library to investigate transduction in S. aureus. We show that the location of bacterial DNA in relation to bacteriophages integrated in the bacterial genome is a key decider of how frequently that DNA is transduced. Based on serial transduction of transposon mutant pools and direct sequencing of bacterial DNA in bacteriophage particles, we demonstrate both lateral and specialized transduction. The use of mutant libraries to investigate the patterns of bacterial DNA transfer between cells could help understand how bacteria evolve virulence and resistance and may ultimately lead to new intervention strategies.

microbiology↗

bioRxiv2019

Human antimicrobial peptide, LL-37, induces non-inheritable reduced susceptibility to vancomycin in Staphylococcus aureus

Antimicrobial peptides (AMPs) are central components of the innate immune system providing protection against pathogens. Yet, serum and tissue concentrations vary between individuals and disease conditions. We demonstrate that the human AMP LL-37 lowers the susceptibility to vancomycin in the community-associated methicillin-resistant S. aureus (CA-MRSA) strain FPR3757 (USA300). Vancomycin is used to treat serious MRSA infections, but treatment failures occur despite MRSA strains being tested susceptible according to standard susceptibility methods. Exposure to physiologically relevant concentrations of LL-37 increased the minimum inhibitory concentration (MIC) of S. aureus towards vancomycin by 75% and resulted in shortened lag-phase and increased colony formation at sub-inhibitory concentrations of vancomycin. Computer simulations using a mathematical antibiotic treatment model indicated that a small increase in MIC might decrease the efficacy of vancomycin in clearing an S. aureus infection. This prediction was supported in a Galleria mellonella infection model, where exposure of S. aureus to LL-37 abolished the antimicrobial effect of vancomycin. Thus, physiologically relevant concentrations of LL-37 reduce susceptibility to vancomycin, indicating that tissue and host-specific variations in LL-37 concentrations may influence vancomycin susceptibility in vivo.

microbiology↗

bioRxiv2018

SosA inhibits cell division in Staphylococcus aureus in response to DNA damage

Inhibition of cell division is critical for cell viability under DNA damaging conditions. In bacterial cells, DNA damage induces the SOS response, a process that inhibits cell division while repairs are being made. In coccoid bacteria, such as the human pathogen Staphylococcus aureus, the process remains poorly understood. Here we have characterized an SOS-induced cell-division inhibitor, SosA, in S. aureus. We find that in contrast to the wildtype, sosA mutant cells continue division under DNA damaging conditions with decreased viability as a consequence. Conversely, overproduction of SosA leads to cell division inhibition and reduced growth. The SosA protein is localized in the bacterial membrane and mutation of an extracellular amino acid, conserved between homologs of other staphylococcal species, abolished the inhibitory activity as did truncation of the C-terminal 30 amino acids. In contrast, C-terminal truncation of 10 amino acids lead to SosA accumulation and a strong cell division inhibitory activity. A similar phenotype was observed upon expression of wildtype SosA in a mutant lacking the membrane protease, CtpA. Thus, the extracellular C-terminus of SosA is required both for cell-division inhibition and for turnover of the protein. Functional studies showed that SosA is likely to interact with one or more divisome components and, without interfering with early cell-division events, halts cell division at a point where septum formation is initiated yet being unable to progress to septum closure. Our findings provide important insights into cell-division regulation in staphylococci that may foster development of new classes of antibiotics targeting this essential process. ImportanceStaphylococcus aureus is a serious human pathogen and a model organism for cell-division studies in spherical bacteria. We show that SosA is the DNA-damage-inducible cell-division inhibitor in S. aureus that upon expression causes cell swelling and cessation of the cell cycle at a characteristic stage post septum initiation but prior to division plate completion. SosA appears to function via an extracellular activity and is likely to do so by interfering with the essential membrane-associated division proteins, while at the same time being negatively regulated by the membrane protease CtpA. This report represents the first description of the process behind cell-division inhibition in coccoid bacteria. As several pathogens are included in this category, uncovering the molecular details of SosA activity and control can lead to identification of new targets for development of valuable anti-bacterial drugs.

microbiology↗

bioRxiv2018

Modelling bacteria-phage interactions driving predation and horizontal gene transfer

Bacteriophages shape microbial communities by predating on them and by accelerating their adaptation through horizontal gene transfer. The former is the basis of phage therapy, whereas the latter drives the evolution of numerous bacterial pathogens. We present a novel computational approach (eVIVALDI - eco-eVolutionary mIcrobial indiViduAL-baseD sImulations) to study phage-bacteria ecological interactions that integrates a large number of processes, including population dynamics, environmental structure, genome evolution, and phage-mediated horizontal transfer. We validate and illustrate the relevance of the model by focusing on three specific questions: the ecological interactions between bacteria and virulent phage during phage and antibiotic therapy, the role of prophages as competitive weapons, and how autotransduction facilitates bacterial acquisition of antibiotic resistance genes upon lysis of antibiotic resistant competitors. Our model recapitulates experimental and theoretical observations and provides novel insights. In particular, we find that environmental structure has a strong effect on community dynamics and evolutionary outcomes in all three case studies. Strong environmental structure, relative to well-mixed environments and especially if antibiotics are heterogeneously distributed, enhances the rate of acquisition of resistance to both phages and antibiotics, and leads to more accurate predictions of the dynamics of lysogen invasion in the gastrointestinal tract. We predicted the co-existence of invaders and resident lysogens in autotransduction under a range of parameters, and validated this key prediction experimentally. By linking ecological and evolutionary dynamics, our modelling approach sheds light on the factors that influence the dynamics of phage-bacteria interactions. It can also be expanded to put forward novel hypotheses, facilitating the design of phage therapy treatments and the assessment of the role of phages in the spread of antibiotic resistance.\n\nAUTHOR SUMMARYIn the face of a growing threat of antibiotic resistant bacteria, bacteriophages have re-emerged as a potential alternative to clinical treatments of infections, as they are efficient bacterial predators. However, bacteriophages can also promote, through a mechanism called transduction, the dissemination of adaptive traits between bacteria, including antibiotic resistance genes. Importantly, these two types of interactions (predation and transduction) can co-occur, which creates difficulties in predicting their outcome. We have developed eVIVALDI (eco-eVolutionary mIcrobial indiViduAL-baseD sImulations), a computational model that allows the simulation of microbial communities with a focus on the mechanisms involved in phage-bacteria interactions, across time and in different types of environments. eVIVALDI can be used to understand the conditions where phages are more likely to be successfully used to eliminate bacteria or, in the other hand, the conditions where they increase the probability of dissemination of adaptive traits. Our research highlights the importance of considering the diverse ways that phage and bacteria interact, and the relevant ecological conditions where these interactions take place, to understand how bacteriophages shape microbial communities and how they can be used as a clinical tool.

microbiology↗