Sara Sharaf, Martina Cappelletti, Marco R Oggioni, Karolin Hijazi
DNA methyltransferases (DNA MTases) are central epigenetic regulators in bacteria and archaea, with functions extending far beyond classical restriction-modification defence. Diverse MTase classes exist, including canonical and phase-variable restriction-modification systems, orphan MTases, and enzymes with currently undefined roles. MTase activity is associated with regulatory outcomes through both direct and indirect mechanisms. Methylation of promoters or regulatory regions can influence transcription, while broader methylome remodelling may affect genome-wide gene expression. These processes generate distinct epigenetic states associated with phenotypic variation. MTase-mediated regulation has been implicated in virulence, colonisation, immune evasion, biofilm formation, motility, stress tolerance, metabolism, and antibiotic susceptibility. In archaea, MTase systems contribute to genome integrity and ecological specialisation, highlighting shared epigenetic principles across domains of life. A major challenge is to move beyond descriptive methylome surveys and correlative analyses toward experimentally validated links between methylation and phenotype. This review synthesises current understanding of prokaryotic DNA methylation, with primary emphasis on experimentally validated phenotypic outcomes. We also incorporate insights from omics-based studies where these provide context or generate testable hypotheses, while noting when evidence is based on inference rather than direct experimental validation, and include underrepresented archaeal systems.
{"title":"Epigenetic Regulation in Prokaryotes: Transcriptional and Phenotypic Outcomes of DNA Methyltransferase activity.","authors":"Sara Sharaf, Martina Cappelletti, Marco R Oggioni, Karolin Hijazi","doi":"10.1093/femsre/fuag014","DOIUrl":"https://doi.org/10.1093/femsre/fuag014","url":null,"abstract":"<p><p>DNA methyltransferases (DNA MTases) are central epigenetic regulators in bacteria and archaea, with functions extending far beyond classical restriction-modification defence. Diverse MTase classes exist, including canonical and phase-variable restriction-modification systems, orphan MTases, and enzymes with currently undefined roles. MTase activity is associated with regulatory outcomes through both direct and indirect mechanisms. Methylation of promoters or regulatory regions can influence transcription, while broader methylome remodelling may affect genome-wide gene expression. These processes generate distinct epigenetic states associated with phenotypic variation. MTase-mediated regulation has been implicated in virulence, colonisation, immune evasion, biofilm formation, motility, stress tolerance, metabolism, and antibiotic susceptibility. In archaea, MTase systems contribute to genome integrity and ecological specialisation, highlighting shared epigenetic principles across domains of life. A major challenge is to move beyond descriptive methylome surveys and correlative analyses toward experimentally validated links between methylation and phenotype. This review synthesises current understanding of prokaryotic DNA methylation, with primary emphasis on experimentally validated phenotypic outcomes. We also incorporate insights from omics-based studies where these provide context or generate testable hypotheses, while noting when evidence is based on inference rather than direct experimental validation, and include underrepresented archaeal systems.</p>","PeriodicalId":12201,"journal":{"name":"FEMS microbiology reviews","volume":" ","pages":""},"PeriodicalIF":12.3,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147503446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jack Orebaugh, Alyssa A Carrell, Larry M York, Melissa A Cregger, Ilenne Del Valle Kessra
Soils are heterogeneous and dynamic systems characterized by complex physical, chemical, and biological interactions. Understanding these interactions is critical, as they influence plant productivity, global biogeochemical cycles, and ecosystem resilience. While ecologists have long studied soils in field, greenhouse, and laboratory settings, their complexity and heterogeneity make it challenging to pinpoint key properties driving biological processes and derive mechanistic insights. Advancements in synthetic biology, which seeks to engineer and control biological processes in soils, have increased the demand for standardized and controllable experimental platforms. These platforms, referred to here as 'synthetic soils', are systems designed to reproduce selected physicochemical characteristics of natural soils in a simplified and defined format, allowing scientists to systematically change soil physicochemical properties (i.e. texture, mineralogy, pH) to study how biological components (i.e. microbes, plants, soil fauna, etc.) respond to, modify, or interact within these controlled environments. This review explores existing synthetic soils, their advantages, limitations, and applications in ecology and synthetic biology, and discusses potential directions for their future development.
{"title":"Synthetic Soils for Ecological and Synthetic Biology Applications.","authors":"Jack Orebaugh, Alyssa A Carrell, Larry M York, Melissa A Cregger, Ilenne Del Valle Kessra","doi":"10.1093/femsre/fuag012","DOIUrl":"https://doi.org/10.1093/femsre/fuag012","url":null,"abstract":"<p><p>Soils are heterogeneous and dynamic systems characterized by complex physical, chemical, and biological interactions. Understanding these interactions is critical, as they influence plant productivity, global biogeochemical cycles, and ecosystem resilience. While ecologists have long studied soils in field, greenhouse, and laboratory settings, their complexity and heterogeneity make it challenging to pinpoint key properties driving biological processes and derive mechanistic insights. Advancements in synthetic biology, which seeks to engineer and control biological processes in soils, have increased the demand for standardized and controllable experimental platforms. These platforms, referred to here as 'synthetic soils', are systems designed to reproduce selected physicochemical characteristics of natural soils in a simplified and defined format, allowing scientists to systematically change soil physicochemical properties (i.e. texture, mineralogy, pH) to study how biological components (i.e. microbes, plants, soil fauna, etc.) respond to, modify, or interact within these controlled environments. This review explores existing synthetic soils, their advantages, limitations, and applications in ecology and synthetic biology, and discusses potential directions for their future development.</p>","PeriodicalId":12201,"journal":{"name":"FEMS microbiology reviews","volume":" ","pages":""},"PeriodicalIF":12.3,"publicationDate":"2026-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147485292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CD169/Siglec-1 is a type-I transmembrane lectin receptor expressed on subcapsular sinus macrophages and activated monocytes, which play a key role in innate immune surveillance and orchestration of adaptive immunity. As a sialic acid-binding immunoglobulin-like lectin (Siglec), CD169 recognizes sialylated gangliosides and glycoconjugates present on surface of several viral envelopes, including HIV-1, SARS-CoV-2 and Ebola virus as well as sialylated bacterial capsules such as those of Neisseria meningitidis and Campylobacter jejuni. Moreover, different viruses were shown to be captured by CD169+ cells which could play distinctive role during infections: they could enhance efficient immune responses, but also facilitate pathogen dissemination through viral capture and transfer to permissive cells. This last mechanism has been well documented for HIV-1, where CD169 mediates viral trans-infection of CD4⁺ T-cells. CD169 expression is rapidly induced by type-I interferons during acute viral infections and has emerged as a valuable biomarker to distinguish viral from bacterial infection, particularly for COVID-19 and influenza. Detectable by flow cytometry, CD169 represents a solid biomarker in clinical settings and possible target in the development of novel prophylactic and therapeutic strategies. Its dual role, protective in host defence yet exploitable by certain pathogens, highlights the need for careful consideration in future therapeutic approaches.
{"title":"Role of myeloid cells expressing CD169/Siglec-1 in host - pathogen interactions.","authors":"Ilona Ronco, Branka Horvat","doi":"10.1093/femsre/fuag013","DOIUrl":"https://doi.org/10.1093/femsre/fuag013","url":null,"abstract":"<p><p>CD169/Siglec-1 is a type-I transmembrane lectin receptor expressed on subcapsular sinus macrophages and activated monocytes, which play a key role in innate immune surveillance and orchestration of adaptive immunity. As a sialic acid-binding immunoglobulin-like lectin (Siglec), CD169 recognizes sialylated gangliosides and glycoconjugates present on surface of several viral envelopes, including HIV-1, SARS-CoV-2 and Ebola virus as well as sialylated bacterial capsules such as those of Neisseria meningitidis and Campylobacter jejuni. Moreover, different viruses were shown to be captured by CD169+ cells which could play distinctive role during infections: they could enhance efficient immune responses, but also facilitate pathogen dissemination through viral capture and transfer to permissive cells. This last mechanism has been well documented for HIV-1, where CD169 mediates viral trans-infection of CD4⁺ T-cells. CD169 expression is rapidly induced by type-I interferons during acute viral infections and has emerged as a valuable biomarker to distinguish viral from bacterial infection, particularly for COVID-19 and influenza. Detectable by flow cytometry, CD169 represents a solid biomarker in clinical settings and possible target in the development of novel prophylactic and therapeutic strategies. Its dual role, protective in host defence yet exploitable by certain pathogens, highlights the need for careful consideration in future therapeutic approaches.</p>","PeriodicalId":12201,"journal":{"name":"FEMS microbiology reviews","volume":" ","pages":""},"PeriodicalIF":12.3,"publicationDate":"2026-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147485233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The bacterial flagellum is an elaborate nanomachine that powers motility in a variety of environments. While recent cryo-electron tomography studies have revealed great complexity as well as diversity in flagellar motor structures, less is known about the components that constitute the auxiliary structures observed in the periplasm for several species. One example is the E-ring, which was first observed in 1979 in Caulobacter crescentus but whose composition has only recently been shown to be a single protein, FlgY and its homologs. Multiple FlgY dimers form a conserved ring-spoke structure encircling the MS-ring, although the impact of the E-ring on motility seems to differ across bacterial phyla. Remarkably, the E-ring is widely present in flagellated species in the Bacteria domain except β- and γ-proteobacteria, suggesting an ancient origin that likely traces back to the last bacterial common ancestor. Future investigation is required to determine the exact role of this conserved structure in motor function, which may reveal mechanisms distinct from the current working model based on Escherichia coli and Salmonella enterica, which lack the E-ring, and also shed light on the architecture and function of the ancestral motor.
{"title":"The Ancient E-ring in Bacterial Flagellar Motors.","authors":"Siqi Zhu, Xueyin Feng, Yanran Liu, Wei Hu, Beile Gao","doi":"10.1093/femsre/fuag011","DOIUrl":"https://doi.org/10.1093/femsre/fuag011","url":null,"abstract":"<p><p>The bacterial flagellum is an elaborate nanomachine that powers motility in a variety of environments. While recent cryo-electron tomography studies have revealed great complexity as well as diversity in flagellar motor structures, less is known about the components that constitute the auxiliary structures observed in the periplasm for several species. One example is the E-ring, which was first observed in 1979 in Caulobacter crescentus but whose composition has only recently been shown to be a single protein, FlgY and its homologs. Multiple FlgY dimers form a conserved ring-spoke structure encircling the MS-ring, although the impact of the E-ring on motility seems to differ across bacterial phyla. Remarkably, the E-ring is widely present in flagellated species in the Bacteria domain except β- and γ-proteobacteria, suggesting an ancient origin that likely traces back to the last bacterial common ancestor. Future investigation is required to determine the exact role of this conserved structure in motor function, which may reveal mechanisms distinct from the current working model based on Escherichia coli and Salmonella enterica, which lack the E-ring, and also shed light on the architecture and function of the ancestral motor.</p>","PeriodicalId":12201,"journal":{"name":"FEMS microbiology reviews","volume":" ","pages":""},"PeriodicalIF":12.3,"publicationDate":"2026-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147443013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Veronika Kuchařová Pettersen, Alise Jany Ponsero, Ching Jian, Alona Riumin, Alexander Kurilshikov, Sabrina John Moyo, Museveni Justine, Claus Klingenberg, Justine Debelius, Mireia Valles-Colomer, Hanna Theodora Noordzij, Alexandra Zhernakova, Katri Korpela, Maria Esteban-Torres, Nele Brusselaers
Early-life microbial exposures are essential for optimal development of human physiology. Yet, understanding of the human microbiome during pregnancy and childhood is still far from being complete. To identify knowledge gaps and establish research priorities, a multidisciplinary expert panel used the Delphi method for consensus development and conducted a literature search on early-life microbiome determinants. Responses from 55 researchers from an online survey were analyzed alongside keyword frequency from 20 501 publications. This approach enabled us to categorize existing evidence and highlight areas requiring investigation. While the main routes for mother-to-child bacterial transmission and their contributions to the newborn microbiome have been studied, many gaps remain. Priority areas include non-bacterial microbes, ecological principles of colonization, environmental and social influences, body sites beyond the gut, and factors affecting the maternal microbiome and its effects on the child's microbiome. Significance of factors such as hygiene habits, non-antibiotic medications, and pollution remains to be uncovered. Knowledge is also limited on postnatal microbial sharing via household contacts and shared environments (e.g. family members, peers) and the contribution of these pathways to microbiome assembly. We hope this report will guide and inspire future research into the early-life microbiome as a modifiable factor in reducing disease risk.
{"title":"Off to a good start: Current gaps and priorities in early-life microbiome research.","authors":"Veronika Kuchařová Pettersen, Alise Jany Ponsero, Ching Jian, Alona Riumin, Alexander Kurilshikov, Sabrina John Moyo, Museveni Justine, Claus Klingenberg, Justine Debelius, Mireia Valles-Colomer, Hanna Theodora Noordzij, Alexandra Zhernakova, Katri Korpela, Maria Esteban-Torres, Nele Brusselaers","doi":"10.1093/femsre/fuag010","DOIUrl":"https://doi.org/10.1093/femsre/fuag010","url":null,"abstract":"<p><p>Early-life microbial exposures are essential for optimal development of human physiology. Yet, understanding of the human microbiome during pregnancy and childhood is still far from being complete. To identify knowledge gaps and establish research priorities, a multidisciplinary expert panel used the Delphi method for consensus development and conducted a literature search on early-life microbiome determinants. Responses from 55 researchers from an online survey were analyzed alongside keyword frequency from 20 501 publications. This approach enabled us to categorize existing evidence and highlight areas requiring investigation. While the main routes for mother-to-child bacterial transmission and their contributions to the newborn microbiome have been studied, many gaps remain. Priority areas include non-bacterial microbes, ecological principles of colonization, environmental and social influences, body sites beyond the gut, and factors affecting the maternal microbiome and its effects on the child's microbiome. Significance of factors such as hygiene habits, non-antibiotic medications, and pollution remains to be uncovered. Knowledge is also limited on postnatal microbial sharing via household contacts and shared environments (e.g. family members, peers) and the contribution of these pathways to microbiome assembly. We hope this report will guide and inspire future research into the early-life microbiome as a modifiable factor in reducing disease risk.</p>","PeriodicalId":12201,"journal":{"name":"FEMS microbiology reviews","volume":" ","pages":""},"PeriodicalIF":12.3,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147389453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Andriana Grafakou, Cas Mosterd, Simon A Jackson, Paul P de Waal, Noël N M E van Peij, Christian Cambillau, Jennifer Mahony, Douwe van Sinderen
Lactococcus lactis and Lactococcus cremoris are cornerstone bacterial species employed in the production of fermented dairy products such as cheese. However, the non-sterile dairy processing environment regularly exposes these lactococci to phage infection. To counteract this phage threat, bacteria have evolved a wide range of defence mechanisms, including so-called abortive infection Abi(-like) systems, of which many (AbiA to AbiZ) were originally discovered in Lactococcus. Recent discoveries have expanded the list of Abi-like systems in Lactococcus species. In this review, we focus on systems historically, phenotypically, or mechanistically classified as Abi, critically examine and revisit their antiphage activity spectrum and interference with the phage lytic cycle, as well as mechanistic insights of lactococcal Abi-like systems as obtained through the study of phage escape mutants. Furthermore, we group various Abi-like systems based on structural superimposition and use predicted domain information to explore or expand on their mechanism of action. Finally, we show that despite many Abi-like systems being discovered due to their presence on plasmids, most anti-phage defence systems appear to be chromosomally encoded in sequenced Lactococcus strains. Our findings support the notion that co-evolution of Lactococcus species with their phages, possibly accelerated by the extensive application of these bacteria in dairy fermentations, has resulted in the acquisition of a diverse array of phage defence mechanisms, including Abi-like systems.
{"title":"Revisiting lactococcal abortive infection-like antiphage systems: Diversity, structures and mechanisms.","authors":"Andriana Grafakou, Cas Mosterd, Simon A Jackson, Paul P de Waal, Noël N M E van Peij, Christian Cambillau, Jennifer Mahony, Douwe van Sinderen","doi":"10.1093/femsre/fuag009","DOIUrl":"https://doi.org/10.1093/femsre/fuag009","url":null,"abstract":"<p><p>Lactococcus lactis and Lactococcus cremoris are cornerstone bacterial species employed in the production of fermented dairy products such as cheese. However, the non-sterile dairy processing environment regularly exposes these lactococci to phage infection. To counteract this phage threat, bacteria have evolved a wide range of defence mechanisms, including so-called abortive infection Abi(-like) systems, of which many (AbiA to AbiZ) were originally discovered in Lactococcus. Recent discoveries have expanded the list of Abi-like systems in Lactococcus species. In this review, we focus on systems historically, phenotypically, or mechanistically classified as Abi, critically examine and revisit their antiphage activity spectrum and interference with the phage lytic cycle, as well as mechanistic insights of lactococcal Abi-like systems as obtained through the study of phage escape mutants. Furthermore, we group various Abi-like systems based on structural superimposition and use predicted domain information to explore or expand on their mechanism of action. Finally, we show that despite many Abi-like systems being discovered due to their presence on plasmids, most anti-phage defence systems appear to be chromosomally encoded in sequenced Lactococcus strains. Our findings support the notion that co-evolution of Lactococcus species with their phages, possibly accelerated by the extensive application of these bacteria in dairy fermentations, has resulted in the acquisition of a diverse array of phage defence mechanisms, including Abi-like systems.</p>","PeriodicalId":12201,"journal":{"name":"FEMS microbiology reviews","volume":" ","pages":""},"PeriodicalIF":12.3,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147354329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mohor Mitra, Sajan, Shrutarshi Paul, Amit Huppert, Edouard Jurkevitch
Predator-prey interactions are intricately linked to ecological systems, from micro-organisms to large animals. Most predator-prey studies use simplified pairwise interactions, constraining our ability to identify general principles. Here, predator-prey choices are examined across scales and levels of environmental complexity. We review current knowledge and emphasize the diversity and complexity of predator-prey systems, point to challenges in integrating them, and propose a framework that could benefit predictive modeling for ecosystem functioning and resilience. To do so, we compare the tools, mechanisms, and strategies deployed by micro- and macro- predators and prey defenses to show that commonalities become identifiable, and suggest structural and functional links between micro- and macro-scales. This provides arguments for both descriptive, and mathematical models. We propose that the use of microbial predators like the Bdellovibrio and like organisms can greatly advance the integration of experimental and mathematical modeling research, as they can provide robust empirical observations of predator-prey interactions tested under multiple conditions and levels of complexity. This facilitates model development, in turn leading to new hypotheses. We conclude by showing examples of current developments, that predator-prey interaction-based knowledge has the potential to provide novel medical tools and to improve environmental and agricultural management.
{"title":"From microbes to animals: a review on prey choice and prey-predator dynamics across organismal scales.","authors":"Mohor Mitra, Sajan, Shrutarshi Paul, Amit Huppert, Edouard Jurkevitch","doi":"10.1093/femsre/fuag004","DOIUrl":"10.1093/femsre/fuag004","url":null,"abstract":"<p><p>Predator-prey interactions are intricately linked to ecological systems, from micro-organisms to large animals. Most predator-prey studies use simplified pairwise interactions, constraining our ability to identify general principles. Here, predator-prey choices are examined across scales and levels of environmental complexity. We review current knowledge and emphasize the diversity and complexity of predator-prey systems, point to challenges in integrating them, and propose a framework that could benefit predictive modeling for ecosystem functioning and resilience. To do so, we compare the tools, mechanisms, and strategies deployed by micro- and macro- predators and prey defenses to show that commonalities become identifiable, and suggest structural and functional links between micro- and macro-scales. This provides arguments for both descriptive, and mathematical models. We propose that the use of microbial predators like the Bdellovibrio and like organisms can greatly advance the integration of experimental and mathematical modeling research, as they can provide robust empirical observations of predator-prey interactions tested under multiple conditions and levels of complexity. This facilitates model development, in turn leading to new hypotheses. We conclude by showing examples of current developments, that predator-prey interaction-based knowledge has the potential to provide novel medical tools and to improve environmental and agricultural management.</p>","PeriodicalId":12201,"journal":{"name":"FEMS microbiology reviews","volume":" ","pages":""},"PeriodicalIF":12.3,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12927660/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146164683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
With the growing severity of antimicrobial resistance (AMR), phage therapy has garnered attention as a novel therapeutic alternative. In particular, phage cocktails, which combine multiple phages, potentially offer broader antimicrobial spectra than single-phage applications and may suppress the emergence of resistant bacteria. This comprehensive review systematically examines cutting-edge technologies and effective strategies for designing phage cocktails. Special attention was given to the combination of phages recognizing different receptors, designs based on phage-bacteria infection network analysis, and synergistic effects with antibiotics. Additionally, the analysis of large-scale clinical studies has identified challenges in practical implementation, including ensuring cocktail stability and addressing immune responses. These insights are expected to contribute to the design of more effective phage cocktails and the establishment of novel therapeutic strategies to address AMR.
{"title":"Phage cocktails: state-of-the-art technologies and strategies for effective design.","authors":"Tomoyoshi Kaneko, Kanata Nakatsuka, Satoshi Tsuneda","doi":"10.1093/femsre/fuaf061","DOIUrl":"10.1093/femsre/fuaf061","url":null,"abstract":"<p><p>With the growing severity of antimicrobial resistance (AMR), phage therapy has garnered attention as a novel therapeutic alternative. In particular, phage cocktails, which combine multiple phages, potentially offer broader antimicrobial spectra than single-phage applications and may suppress the emergence of resistant bacteria. This comprehensive review systematically examines cutting-edge technologies and effective strategies for designing phage cocktails. Special attention was given to the combination of phages recognizing different receptors, designs based on phage-bacteria infection network analysis, and synergistic effects with antibiotics. Additionally, the analysis of large-scale clinical studies has identified challenges in practical implementation, including ensuring cocktail stability and addressing immune responses. These insights are expected to contribute to the design of more effective phage cocktails and the establishment of novel therapeutic strategies to address AMR.</p>","PeriodicalId":12201,"journal":{"name":"FEMS microbiology reviews","volume":" ","pages":""},"PeriodicalIF":12.3,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12776354/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145700068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Denisa Vondrova, Sabrina Laura Mugni, Jan Blumenstein, Clara Kasiztky, Federico Sisti, Julieta Fernández, Jana Kamanova
Cyclic di-GMP (c-di-GMP) is a highly conserved bacterial second messenger that regulates important processes such as motility, biofilm formation and virulence. In this review, we investigate the architecture and regulatory functions of c-di-GMP signaling in classical Bordetella species, including B. bronchiseptica, B. parapertussis and B. pertussis. We examine how the c-di-GMP signaling pathway interacts with the BvgAS two-component system and other signaling pathways to coordinate virulence gene expression and surface-associated behaviors in these respiratory pathogens. In particular, we highlight the functions of characterized diguanylate cyclases (DGCs), phosphodiesterases (PDEs) and dual-domain proteins, focusing on regulatory modules such as the BdcA-DdpA scaffold complex, the oxygen-sensing DGC BpeGReg and the LapD-LapG proteolytic switch that controls BrtA adhesin. We also propose a model for the function of BvgR, a PDE-like protein lacking catalytic residues, and discuss how c-di-GMP suppresses the type III secretion system. Importantly, we highlight the diversity of the c-di-GMP network in classical Bordetella species, likely reflecting their evolutionary specialization. To conclude, we outline important open questions and suggest future research directions, including the identification of sensory ligands and c-di-GMP effectors. Overall, our review illustrates the importance of c-di-GMP as a critical, but still incompletely understood, regulatory hub in Bordetella pathogenesis.
环二gmp (c-di-GMP)是高度保守的细菌第二信使,调节重要的过程,如运动,生物膜形成和毒力。在本文中,我们研究了c-di-GMP信号的结构和调控功能在经典的博德氏杆菌,包括B. bronchiseptica, B. parpertussis和B. pertussis。我们研究了c-di-GMP信号通路如何与BvgAS双组分系统和其他信号通路相互作用,以协调这些呼吸道病原体的毒力基因表达和表面相关行为。特别地,我们强调了特征二胍酸环化酶(DGCs),磷酸二酯酶(PDEs)和双结构域蛋白的功能,重点关注调控模块,如BdcA-DdpA支架复合物,氧传感DGC BpeGReg和控制BrtA粘附素的LapD-LapG蛋白水解开关。我们还提出了BvgR(一种缺乏催化残基的pde样蛋白)的功能模型,并讨论了c-di-GMP如何抑制III型分泌系统。重要的是,我们强调了经典博德泰拉物种中c-di-GMP网络的多样性,这可能反映了它们的进化专业化。最后,我们概述了重要的开放性问题,并提出了未来的研究方向,包括感觉配体和c-二gmp效应器的鉴定。总的来说,我们的综述说明了c-di-GMP在博德特菌发病机制中作为一个关键但仍未完全理解的调控枢纽的重要性。
{"title":"Architecture and regulatory functions of c-di-GMP signaling in classical Bordetella species.","authors":"Denisa Vondrova, Sabrina Laura Mugni, Jan Blumenstein, Clara Kasiztky, Federico Sisti, Julieta Fernández, Jana Kamanova","doi":"10.1093/femsre/fuaf065","DOIUrl":"10.1093/femsre/fuaf065","url":null,"abstract":"<p><p>Cyclic di-GMP (c-di-GMP) is a highly conserved bacterial second messenger that regulates important processes such as motility, biofilm formation and virulence. In this review, we investigate the architecture and regulatory functions of c-di-GMP signaling in classical Bordetella species, including B. bronchiseptica, B. parapertussis and B. pertussis. We examine how the c-di-GMP signaling pathway interacts with the BvgAS two-component system and other signaling pathways to coordinate virulence gene expression and surface-associated behaviors in these respiratory pathogens. In particular, we highlight the functions of characterized diguanylate cyclases (DGCs), phosphodiesterases (PDEs) and dual-domain proteins, focusing on regulatory modules such as the BdcA-DdpA scaffold complex, the oxygen-sensing DGC BpeGReg and the LapD-LapG proteolytic switch that controls BrtA adhesin. We also propose a model for the function of BvgR, a PDE-like protein lacking catalytic residues, and discuss how c-di-GMP suppresses the type III secretion system. Importantly, we highlight the diversity of the c-di-GMP network in classical Bordetella species, likely reflecting their evolutionary specialization. To conclude, we outline important open questions and suggest future research directions, including the identification of sensory ligands and c-di-GMP effectors. Overall, our review illustrates the importance of c-di-GMP as a critical, but still incompletely understood, regulatory hub in Bordetella pathogenesis.</p>","PeriodicalId":12201,"journal":{"name":"FEMS microbiology reviews","volume":" ","pages":""},"PeriodicalIF":12.3,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12805831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145833328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Staphylococcus epidermidis is a highly adapted commensal of the human skin. However, it can also cause severe infections by exploiting skin fissures to establish antibiotic-resistant biofilms on implanted medical devices, which may subsequently release bacteria into the bloodstream. Emerging studies increasingly highlight the critical role of metabolic status and regulatory mechanisms in governing biofilm formation and, consequently, the pathogenic potential of S. epidermidis. This review examines its metabolic adaptability across different environments, emphasizing how environmental factors such as nutrient availability, oxygen levels, pH, and temperature, shape central metabolic pathways. It covers sugar, amino acid, and fatty acid utilization, regulatory networks controlling respiration, fermentation, and polysaccharide intercellular adhesin (PIA)-mediated biofilm formation, and strategies for surviving host-derived oxidative and nitrosative stresses. Comparisons with S. aureus further reveal species-specific differences in metabolism, nutrient acquisition, and regulation. Altogether, the mechanistic insights provide a comprehensive overview of S. epidermidis physiology in both commensal and infection-associated contexts.
{"title":"Metabolic and regulatory adaptations of Staphylococcus epidermidis to host stresses.","authors":"Sandra M Carvalho, Lígia M Saraiva","doi":"10.1093/femsre/fuag008","DOIUrl":"10.1093/femsre/fuag008","url":null,"abstract":"<p><p>Staphylococcus epidermidis is a highly adapted commensal of the human skin. However, it can also cause severe infections by exploiting skin fissures to establish antibiotic-resistant biofilms on implanted medical devices, which may subsequently release bacteria into the bloodstream. Emerging studies increasingly highlight the critical role of metabolic status and regulatory mechanisms in governing biofilm formation and, consequently, the pathogenic potential of S. epidermidis. This review examines its metabolic adaptability across different environments, emphasizing how environmental factors such as nutrient availability, oxygen levels, pH, and temperature, shape central metabolic pathways. It covers sugar, amino acid, and fatty acid utilization, regulatory networks controlling respiration, fermentation, and polysaccharide intercellular adhesin (PIA)-mediated biofilm formation, and strategies for surviving host-derived oxidative and nitrosative stresses. Comparisons with S. aureus further reveal species-specific differences in metabolism, nutrient acquisition, and regulation. Altogether, the mechanistic insights provide a comprehensive overview of S. epidermidis physiology in both commensal and infection-associated contexts.</p>","PeriodicalId":12201,"journal":{"name":"FEMS microbiology reviews","volume":" ","pages":""},"PeriodicalIF":12.3,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147364492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}