Recent groundbreaking research spearheaded by scientists from Heinrich Heine University Düsseldorf (HHU), the University of Tübingen, along with contributions from Gießen University, Freiburg University, the Max Planck Institute for Biology Tübingen, the US National Institutes of Health, and the New Jersey Medical School, has brought to light a previously uncharacterized family of signaling proteins. These proteins are ubiquitously distributed throughout the bacterial kingdom and are pivotal in regulating the dynamic behavior of bacterial motility mechanisms and DNA uptake.

Published in the prestigious journals Cell Discovery and Proceedings of the National Academy of Sciences (PNAS), this research elucidates the intricate molecular dialogue governed by second messenger molecules, specifically the cyclic dinucleotides c-di-GMP and c-di-AMP. At the heart of this regulatory nexus lies the newly identified receptor protein ComFB. This receptor mediates the bacterial response to cyclic dinucleotides, thereby finely tuning both motility and DNA competence processes. The findings underscore the sophistication of bacterial intracellular signaling networks and their evolutionary conservation.

The discovery of ComFB reveals a versatile mechanism through which bacteria perceive and integrate environmental and cellular signals. This receptor protein’s ability to bind both c-di-GMP and c-di-AMP with high specificity indicates a dual regulatory role, modulating flagellar and pilus activity as well as the uptake of extracellular DNA — a process known as natural competence. Natural competence is vital for genetic diversity and horizontal gene transfer, allowing bacteria to quickly adapt to new stressors such as antibiotics, thereby exacerbating the challenge of antimicrobial resistance.

PhD student Sherihan Samir, leading the experimental investigations, highlights that the ComFB proteins from cyanobacteria, Bacillus subtilis, and the notorious pathogen Vibrio cholerae demonstrate remarkable precision in sensing second messenger molecules and translating these signals into functional changes in bacterial behavior. This interplay represents a paradigm shift in our understanding of how bacteria coordinate complex physiological functions using minimalistic molecular tools.

Professor Khaled Selim, the principal investigator, explains that c-di-AMP belongs to a novel class of cyclic dinucleotide second messengers whose roles had remained largely elusive until now. Their research successfully connects c-di-AMP signaling with the regulation of natural competence, mediated by ComFB proteins. This regulatory axis not only governs motility but also impacts the integration of foreign DNA into bacterial genomes, influencing traits such as virulence and resistance.

Understanding bacterial natural competence through the lens of ComFB and cyclic dinucleotide signaling has profound implications. The capacity for bacteria to uptake and incorporate genetic material facilitates rapid genetic diversification, offering a survival advantage in fluctuating environments. Moreover, it accentuates the threat posed by multi-drug resistant bacteria, as genes conferring resistance can disseminate swiftly across bacterial populations and species boundaries via competence-driven DNA uptake.

The breadth of bacteria employing this signaling mechanism remains an open question. Researchers are keen to explore whether clinically significant pathogens utilize ComFB-mediated signaling pathways. Such insights could herald novel antimicrobial strategies, targeting the molecular machinery of bacterial competence and motility, thereby mitigating the spread of antibiotic resistance.

The contractile pilus machinery, a critical motility organelle involved in DNA uptake, is evidently regulated by ComFB in response to cyclic dinucleotides. Visualization and structural studies, enhanced by innovative AI-generated imaging, have elucidated the conformational dynamics underpinning this mechanism. This detailed molecular understanding paves the way for targeted interventions that disrupt pathogenic bacterial communication and movement.

Furthermore, the interdisciplinary collaboration across multiple universities and research institutions underscores the complexity and significance of this discovery. Integrating microbiology, biochemistry, structural biology, and advanced imaging techniques, the research exemplifies how multidisciplinary efforts can unravel fundamental biological processes with far-reaching implications.

As scientific inquiry advances, the potential to exploit second messenger systems like c-di-AMP and c-di-GMP in clinical settings becomes increasingly tangible. By manipulating bacterial signaling pathways, it may become feasible to attenuate virulence, inhibit DNA uptake, and ultimately stem the tide of antibiotic resistance — one of the most pressing global health challenges of the 21st century.

These findings not only deepen our molecular comprehension of bacterial adaptability and pathogenicity but also open new horizons for translational research. The identification of ComFB as a central node in bacterial signal transduction emphasizes the intricate balance between motility and genetic exchange, a balance that sustains bacterial evolution and ecological success.

In conclusion, this seminal work expands the frontier of bacterial cell biology, spotlighting the intricate signaling mechanisms that govern critical aspects of bacterial life. As researchers continue to probe the depths of microbial communication and competence, the insights gained from the ComFB-cyclic dinucleotide axis promise to inspire innovative therapeutic strategies and enhance our ability to combat infectious diseases effectively.

Subject of Research: Regulation of bacterial motility and DNA uptake by cyclic dinucleotide second messengers via the ComFB receptor protein.

Article Title: ComFB, a new widespread family of c-di-NMP receptor proteins

News Publication Date: 18-Sep-2025

Web References:

• PNAS Article DOI: 10.1073/pnas.2513041122
• Cell Discovery Article DOI: 10.1038/s41421-025-00816-x

References:
Samir S, Elshereef AA, Alva V, et al. ComFB, a new widespread family of c-di-NMP receptor proteins. Proc Natl Acad Sci USA. 2025;122(38).
Samir S, Doello S, Enkerlin AM, et al. The second messenger c-di-AMP controls natural competence via ComFB signaling protein. Cell Discov. 2025;11(65).

Image Credits: HHU / Khaled Selim

Keywords: Cellular physiology, Flagella, Cyclic dinucleotides, Bacterial motility, DNA uptake, Natural competence, Antibiotic resistance, Signal transduction, ComFB receptor, c-di-GMP, c-di-AMP, Bacterial pathogenicity

Polymers are long chains of repeating molecular units that, in their passive form, are well-studied within polymer physics. Traditionally, the complexity of entangled polymers has been characterized by the tube model. This model posits that each polymer chain moves within a virtual tube formed by neighboring chains, leading to constrained, snake-like diffusive motion known as reptation. In passive systems, the disentanglement time scales predictably with the length of the polymer, a relationship mathematically captured by universal scaling laws and their characteristic exponents. This foundational framework earned Pierre-Gilles de Gennes the Nobel Prize in Physics in 1991.

However, nature frequently deals with polymers that are not passive but active—chains composed of elements capable of self-propulsion and autonomous motion. Earthworm clusters and the writhing tentacles of the lion’s mane jellyfish offer vivid macroscopic examples where internal activity generates dynamic entanglement, conferring emergent rigidity and making unentanglement practically impossible. Similarly, robotic grippers mimicking these biological systems employ multiple synthetic flexible arms to grip objects by leveraging active entanglements. At even smaller scales, such active polymers are ubiquitous inside living cells, orchestrating a myriad of biological processes.

Until now, the influence of such intrinsic activity on the canonical tube model remained an open question. How does self-propulsion alter the fundamental scaling laws of entangled polymer systems? The research team addressed this challenge by deploying large-scale three-dimensional computer simulations that model clusters of flexible polymers endowed with active motion. Here, activity represents internally generated forces causing continuous, spontaneous motion of individual chains, distinct from thermal fluctuations alone.

The simulations revealed that active motion fundamentally modifies the long-standing universal scaling laws, producing an entirely different exponent governing the disentanglement times. Contrary to intuitive expectations that active movement would facilitate rapid disengagement, the researchers found that internal activity fosters robust new entanglements. These grip-like interactions amplify the effective stiffness of the entire collective, transforming what would otherwise be a fluidic polymer gel into a dynamically arrested, solid-like state.

This profound shift in behavior demanded a rethinking of the classical tube model. By introducing an augmented theoretical framework incorporating active forces and internal gripping, the researchers formulated a new tube model capable of accurately describing the emergent viscoelastic properties. This innovation bridges passive polymer physics with the active realm, illuminating how activity serves as a mechanism to self-entangle and freeze polymer assemblies in space and time.

Dr. Davide Breoni, lead author and former doctoral student under Professor Hartmut Löwen, remarked on the painstaking computational effort involved: preparing cluster simulations across a spectrum of polymer lengths required meticulous parameter tuning and immense computational resources. Nonetheless, this allowed precise numerical extraction of the modified scaling laws, conclusively demonstrating the systematic dependence of relaxation times on chain length under active conditions.

Further emphasizing the paradigm shift, Dr. Suvendu Mandel, a postdoctoral researcher involved in the project, noted that their findings overturn conventional assumptions. While activity is widely considered a facilitator of structural relaxation and enhanced dynamism, their results showcase that in certain soft matter systems, collective activity paradoxically enforces rigidity through persistent entanglement and mutual blockage.

Professor Löwen highlighted practical implications, envisioning the design of novel “smart materials” whose mechanical properties can be rapidly switched on demand by toggling internal activity. Such materials could revolutionize soft robotics, adaptive coatings, and bioengineered scaffolds, where controlling the transition between fluid-like flexibility and solid-like stiffness is paramount.

The study further connects to broader biological contexts, providing a theoretical basis for the mechanics of living systems composed of self-driven filaments, such as cytoskeletal networks and bacterial colonies. Understanding how activity induces mechanical rigidity may inform biomedical strategies aimed at manipulating tissue stiffness or combating biofilm formation.

From a theoretical standpoint, the new active tube model enriches the toolkit of polymer physicists by integrating nonequilibrium driving forces into a fundamentally equilibrium-based framework. This expansion challenges and extends decades of established knowledge, provoking renewed exploration into the physics of active soft matter.

Technologically, the insight into activity-induced stress plateaus opens pathways for engineering materials with tunable rheology. For example, soft gels that stiffen in response to biochemical triggers could find applications in drug delivery systems, responsive implants, and wearable electronics, marking a paradigm shift in material functionality.

As the team continues to investigate the interplay between polymer flexibility, activity strength, and entanglement topology, future studies will explore the transition thresholds between fluid, glassy, and solid-like regimes in active polymer solutions. These insights promise to further unravel the mysteries of living matter and its synthetic mimics.

In conclusion, this landmark research not only refines our understanding of polymer physics in active systems but also bridges fundamental science with tangible applications in materials science and biology. By demonstrating how active motion can paradoxically reinforce entanglement and solidity, it reshapes how scientists conceive dynamic assemblies, both in nature and the laboratory.

Subject of Research: Dynamics and scaling laws of entangled active flexible polymer chains and their implications for living systems and smart materials.

Article Title: Giant Activity-Induced Stress Plateau in Entangled Polymer Solutions

News Publication Date: 12 June 2025

Web References: DOI 10.1038/s41467-025-60210-9

References:
Breoni, D., Kurzthaler, C., Liebchen, B., Löwen, H., & Mandal, S. (2025). Giant Activity-Induced Stress Plateau in Entangled Polymer Solutions. Nature Communications, 16, 5305.

Image Credits: HHU/Davide Breoni

Keywords

Soft matter physics, active polymers, entanglement dynamics, active soft matter, living worm clusters, flexible polymer filaments, scaling laws, tube model, viscoelasticity, smart materials, biological polymers, polymer physics