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Open research questions in Bacteriophages and microbial interactions

44 unresolved questions extracted from the limitations and future-work sections of 326 Bacteriophages and microbial interactions papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • Selective import of phage-encoded proteins into this nucleus is critical for successful infection, yet the mechanisms governing this specificity remain incompletely understood.

    Characterizing Import of RNA Polymerase into a Phage Nucleus 2310316 · 2026 · DOI

  • While the precision and the natural occurrence of phages in the environment have drawn attention to phages as new "drugs" in the time of accelerated antibiotic resistance, it remains poorly understood how phage treatment impacts the community of organisms composing the microbiome.

    Bacteriophage treatment of Pseudomonas aeruginosa PA14 infection does not alter the native microbiome of Caenorhabditis elegans · 2026 · DOI

  • The utility of bacteriophages as recognition elements in diverse biosensing platforms is well supported by the literature. Nevertheless, realizing widespread implementation across food safety, environmental monitoring, and clinical diagnostics requires further advancement in several areas. Recognition element optimization remains important. Kumar Discover Chemistry (2026) 3:349 Page 20 of 26 Many sensors rely on native phages or naturally derived structures, but variability in binding efficiency, stability, and tolerance to background matrices exists among phage batches or strains. Engineering phages via synthetic biology or genome editing tools (e.g., CRISPR-Cas), or applying directed evolution, can yield recognition reagents with broader host ranges, stronger affinities, enhanced structural stability, and improved suitability for immobilization. Phage RBPs and CBDs offer compact size, facile expression and purification, and are better suited for high-density, reusable sensor interfaces. Nanomaterial-assisted approaches and multimodal platform design are also critical to enhance sensitivity and signal generation. Functionalizing phage elements with highperformance materials such as metal nanoparticles, carbon nanostructures, or MOFs can markedly boost electrical, optical, or mass-sensing transduction efficiency. Integrating multiple sensing modalities, electrochemical, optical, and mass-based, allows complementary signal validation, improving detection reliability and resistance to interference in complex samples. Given the global emphasis on public health and food safety surveillance, POCT technologies are increasingly vital for disease control, pollution monitoring, and food inspection. To satisfy needs in resource-limited settings, future efforts should prioritize localization, portability, and microfluidic integration. Embedding phage recognition elements into paper-based microfluidic chips, lateral flow assays, or portable microfluidic devices can enable sample preprocessing, target enrichment, and concentration, substantially improving sensitivity for low-abundance targets in complex matrices. Coupling these formats with smartphone-based imaging and data readout systems could establish practical on-site testing solutions appropriate for constrained environments. Bacteriophages exhibit greater environmental stability than many conventional biorecognition molecules; however, their performance in complex biological matrices remains a significant challenge. Proteins, enzymes, salts, and other interfering substances that are present in biological samples like blood, serum, milk, wastewater, and food extracts affect phage viability, adsorption efficiency, and target-binding capability.

    Bacteriophage based biosensors for advanced pathogen detection and diagnostic applications · 2026 · DOI

  • Ultra-small Nanobdellati (initially called DPANN) archaea rely on larger hosts for survival, yet their effects on host eco-physiology and their interactions with infecting viruses have not yet been examined experimentally.

    A Tripartite Co-culture System Reveals Defensive Mutualism Between a Nanobdellati Symbiont and Its Host · 2026 · DOI

  • Escherichia coli HS - a commensal strain used as a model in gut colonization studies - has not been reported as a host for dsDNA phages and is resistant to more than 100 coliphages from the BASEL collection.

    Phages infecting the common gut commensal Escherichia coli HS reveal tropism for its Klebsiella-like capsule · 2026 · DOI

  • Despite the severity of SRP on potato production, little is known about the genetic diversity of SRPs in Denmark, and since only few isolates are available, the possibility to design a broadly effective phage cocktail is limited.

    Danish profile of soft rot Pectobacteriaceae; A three-year field sampling study proving several clonal clades of soft rot isolates across diverse locations implicating a common origin · 2026 · DOI

  • Yet the bacterial genetic determinants that govern phage-host specificity and infection success remain poorly understood, particularly in clinically and ecologically important genera such as Klebsiella where prior receptor characterization has been almost entirely limited to capsulated strains.

    Cross-family and phage-specific gene requirements for Klebsiella infection revealed by scalable RB-TnSeq genetic screens · 2026 · DOI

  • BackgroundBacteriophages are recognized modulators of microbiome composition and function, yet their role in the porcine upper respiratory tract, a primary gateway for pathogen colonization in the post-weaning period, remains unexplored.

    Paired viromics resolves the modular ecological architecture of the swine nasopharyngeal phageome · 2026 · DOI

  • Experimental characterization of the cloud isolate Curtobacterium nubigenum MPC39 further revealed pronounced resistance to UV-B radiation and the presence of an inducible prophage, Curtobacterium phage vB_CnuS_Cirrus1 assigned to the new viral family Nebulaviridae, which could be validated in transmission electron microscopy.

    Virus-host interactions and viral population dynamics across atmospheric cloud events · 2026 · DOI

  • Jumbo phages, with their large genomes, giant virion sizes, and intri- cate lifecycles, are redefining long-held assumptions about bacter- iophage complexity. Despite major advances in recent years, our understanding of jumbo phage biology remains limited, with many fundamental questions still unanswered. Are there additional, yet undiscovered, viral organelles encoded by jumbo phages? How many eukaryotic-like characteristics of jumbo phages might still be uncov- ered? What evolutionary pressures shape the genomic architecture and complexity of jumbo phages? How does the viral genome transit from the EPI vesicle into the phage nucleus? How are nucleotides, mRNAs, and proteins selectively imported and exported across the EPI vesicle and the nucleus shell? How do jumbo phages evade or suppress diverse host immune systems? What is the function of the small, uncharacterized genes present in many jumbo phage genomes? Are there undiscovered classes of MGEs encoded within, or parasitiz- ing, jumbo phages? What is the therapeutic potential of jumbo phages in overcoming multidrug-resistant infections? To what extent will structural prediction tools (e.g., AlphaFold, Foldseek) and metage- nomic mining reveal unknown jumbo phage functions? Such questions may guide future research priorities in exploring the jumbo phage jungle.

    The biology of jumbo phages · 2026 · DOI

  • In recent years, endolysin research has received increasing attention due to the rising global burden of multidrug-resis- tant bacterial infections and the declining effectiveness of traditional antibiotics. Endolysins exhibit strong antibacte- rial activity against Gram-positive bacteria and have made progress in clinical development, with several candidates now in Phase I-III trials. The high specificity and protein- aceous nature of endolysins allow targeted bacteria killing with minimal impact on the commensal microflora, thereby reducing dysbiosis and resistance development. Endolysins demonstrate synergistic interactions with conventional anti- biotics, providing a promising strategy to strengthen exist- ing antimicrobial therapies. Advances in protein engineering Page 17 of 22 359 and delivery technologies have enabled endolysins to over- come biological barriers, thereby enhancing their stability, pharmacokinetics, and activity against Gram-negative bac- teria, thereby expanding their translational scope. Despite these advantages, some challenges remain, including limited serum stability, proteolytic degradation, short half-life, poor tissue penetration, and immunogenic- ity. To enable regulatory approval and clinical translation, standardized PK/PD models, optimized dosing regimens, and scalable manufacturing processes are required. In par- allel, robust long-term safety studies and well-designed clinical trials will be necessary to validate systemic use of endolysins. Importantly, endolysins are unlikely to replace antibiot- ics in the management of systemic infectious diseases in the foreseeable future. Instead, endolysins are expected to become part of standard care in specific areas such as res- cue therapy for multidrug-resistant infections, management of device-associated and biofilm-related infections, and for localized treatments such as catheter-directed, topical, and inhaled therapies. In these contexts, their targeted mecha- nism of action and rapid bacteriolytic activity provide clear therapeutic advantages and clinical feasibility. In conclusion, endolysins represent one of the most cred- ible and strategically important innovations in the evolving anti-infective landscape. With continued interdisciplinary advances in microbiology, immunology, protein engineer- ing, nanotechnology, and clinical sciences, endolysins are poised to transition from experimental biologics to clinically integrated therapeutics, redefining antibacterial therapy through targeted, combination-based, and infection context- specific interventions rather than antibiotic replacement. Acknowledgements The first author gratefully acknowledges the CAMO-NET project for providing fellowship support. The author also sincerely thanks the Department of Medical Microbiology, PGIMER, Chandigarh, for providing the necessary facilities and support through- out the preparation of this review article. Author contributions K.S. conceived the review, conducted the litera- ture survey, synthesised the information, wrote the original draft, and designed the visualisations. N.C. and H.K. provided critical feedback and assisted in manuscript editing. N.T. provided supervision and con- tributed to the final review and editing of the manuscript. All authors have read and approved the final version of the manuscript. Funding Not applicable. Data availability No datasets were generated or analysed during the current study.

    Phage endolysin therapy: a modern antimicrobial strategy against highly drug-resistant superbugs · 2026 · DOI

  • The use of endolysins in clinical settings faces several unresolved challenges with pharmacokinetics and pharmacodynamics (PK/PD). These challenges include limited tissue penetration, a short half-life in systemic circulation, and the absence of clear dosing plans. Pharmacokinetic analysis of the modified endolysin LysECD7-SMAP in mice showed a short serum half-life (t1/2 = 12.5 min). However, therapeutic concentrations persisted for up to 60 min after intravenous injection. This duration is sufficient to achieve antibacterial effectiveness, even at 10 times higher (125 mg/kg) and 40 times higher (500 mg/kg) doses. The preparation did not trigger an immune response and only caused minor, reversible allergic reactions after repeated use (Antonova et al. 2024). Genetic fusion of the albumin-binding and dimerization domains to the engineered endolysin ML06 significantly improved its pharmacokinetics. ML06-ABP2 and HDD-ML06 had longer serum half-lives. HDD-ML06 had a higher Cmax of 22.2 µg/mL than ML06 (< 5 µg/mL), while retaining antibacterial activity in blood serum (Antonova et al. 2025). Collectively, these studies demonstrate that rational protein engineering and chemical modification strategies, including PEGylation and advanced delivery systems such as nanocarriers, represent viable approaches to overcome PK/PD limitations. Delivery challenges in Gram-negative bacteria Another main translational challenge is the outer membrane of Gram-negative bacteria, which restricts endolysin access to the underlying peptidoglycan layer. Gram-negative endolysins can be effectively advanced through genetic engineering and delivery strategies, including domain swapping, fusion with antimicrobial or sensitizer peptides, and receptor-targeted constructs, which enable outer membrane penetration while preserving bacteriolytic activity.

    Phage endolysin therapy: a modern antimicrobial strategy against highly drug-resistant superbugs · 2026 · DOI

  • One limitation of this study is that O-antigen typing of the Klebsiella pneumoniae strains was not performed. Although the isolated phages exhibited broad lytic activ- ity across multiple capsular (K) types, the absence of O-antigen characterization limits definitive conclu- sions regarding the precise bacterial surface receptor(s) involved in phage adsorption. Since phages capable of infecting diverse capsular types may utilize alternative surface structures such as lipopolysaccharide compo- nents or outer membrane proteins, inclusion of O-anti- gen profiling would have provided additional insight into receptor specificity and host–phage interactions. Future studies incorporating detailed surface antigen charac- terization will help elucidate the molecular basis of host recognition and further refine the therapeutic potential of these phages.

    Isolation and characterization of novel bacteriophages with broad-spectrum lytic activity against carbapenem-resistant Klebsiella pneumoniae capsular pathotypes K1, K2, K3, K5, and K20 · 2026 · DOI

  • The dual-phage cocktail strategy (MRABP9 plus a second phage targeting resistant strains) showed improved efficacy against CRAB infection, but extension of this dual-phage approach to other bacterial infections with different capsule types and resistance mechanisms remains unexplored and requires tailored validation.

    A conserved KL2-capsule-related phage-resistant mechanism in carbapenem-resistant Acinetobacter baumannii is surmountable by a rationally selected dual-phage cocktail · 2026 · DOI

  • Certain MRABP9-resistant A. baumannii strains exhibited elevated minocycline resistance, indicating that phage resistance does not uniformly incur fitness costs; case-specific evaluations of phage-antibiotic combinations are needed to identify which antibiotic-phage pairs demonstrate synergistic effects versus antagonistic cross-resistance patterns in carbapenem-resistant A. baumannii.

    A conserved KL2-capsule-related phage-resistant mechanism in carbapenem-resistant Acinetobacter baumannii is surmountable by a rationally selected dual-phage cocktail · 2026 · DOI

  • SNPs in the baeS gene were identified as putatively mediating dual-phage resistance in three sequenced DPR strains, but the mechanistic link between baeS mutations and alterations in bacterial membrane molecules remains unconfirmed; construction of baeS gene knockout and complementation strains in MRAB11 failed due to plasmid exclusion, preventing direct functional validation of this resistance mechanism.

    A conserved KL2-capsule-related phage-resistant mechanism in carbapenem-resistant Acinetobacter baumannii is surmountable by a rationally selected dual-phage cocktail · 2026 · DOI

  • The study examined KL2 A. baumannii isolates from only three Chinese cities (111 clinical isolates); global extrapolation of dual-phage cocktail efficacy against KL2 A. baumannii requires geographic validation across diverse clinical populations and regions outside China to confirm the worldwide applicability of this phage-resistance mechanism.

    A conserved KL2-capsule-related phage-resistant mechanism in carbapenem-resistant Acinetobacter baumannii is surmountable by a rationally selected dual-phage cocktail · 2026 · DOI

  • We hope that the free and open-source, searchable nature of AntiDefenseFinder will enable the field to identify the full repertoire of anti-defense systems, especially in understudied MGEs.

    Exploring the diversity of anti-defense systems across prokaryotes, phages and mobile genetic elements · 2024 · DOI

  • anginosus strains carry prophages, lysogen induction by external stimuli has not been demonstrated, and phage-mediated infection or lysis of this species has not been reported.

    Fluoroquinolone-Triggered Prophage Induction in Streptococcus anginosus Reveals Lytic Cycle, CRISPR-Prophage Interplay, and the potential for Cross-Species Horizontal Gene Transfer · 2026 · DOI

  • Efficient and repeatable DNA extraction, sequencing, and bioinformatics processes are critical for safety assessments but remain poorly defined.

    Long read and short read whole genome sequencing are equivalent for genomic characterisation of bacteriophage: considerations for high throughput analysis · 2026 · DOI

  • Additionally, the impact of sequencing platform choice and DNA extraction methods on downstream genomic analyses is not well understood.

    Long read and short read whole genome sequencing are equivalent for genomic characterisation of bacteriophage: considerations for high throughput analysis · 2026 · DOI

  • A core but rarely examined assumption of these screens is that fitness is measured in an asocial environment, where each mutant succeeds or fails on its own.

    Sociality changes Gene Essentiality · 2026 · DOI

  • Using paired quorum-sensing microarray and Tn-seq data from Pseudomonas aeruginosa, we find that quorum-sensing regulated genes are over-represented among genes scored as non-essential, confirming that social genes are under-reported as essential.

    Sociality changes Gene Essentiality · 2026 · DOI

  • Giant viruses play crucial ecological roles in aquatic ecosystems, yet their evolutionary dynamics in response to environmental changes, particularly in freshwater environments, are not well understood.

    Vicennial metagenomic time series unveils evolutionary dynamics of giant viruses in a freshwater ecosystem · 2026 · DOI

  • While some phages bind to host derived mucins at mucosal surfaces, the functional consequences of soluble mucin glycans for phage-host interactions remain incompletely understood.

    Slow to Start, Free at Last: Dual Effects of Mucin on Escherichia coli Phage T4 · 2026 · DOI

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44 open questions have been extracted from the limitations and future-work passages of 326 Bacteriophages and microbial interactions papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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