Beyond Traditional Targets: Harnessing Natural Antimicrobials from Bacteria

In a groundbreaking study published in Nature Structural & Molecular Biology, researchers at the Icahn School of Medicine at Mount Sinai have unlocked a novel approach to combat bacterial infections by harnessing the power of the bacterial defense mechanism known as the cyclic oligonucleotide-based antiphage signaling system (CBASS).

Unveiling Bacterial Defense Mechanisms

Led by co-senior authors Aneel Aggarwal, Ph.D., and Olga Rechkoblit, Ph.D., the research team embarked on a quest to decipher the activation mechanism of CBASS, a natural defense system employed by bacteria to fend off viral attacks. Through meticulous structural analysis and a series of comprehensive assays, the researchers sought to elucidate how CBASS could be manipulated to limit bacterial infections—an urgent imperative in the face of escalating antibiotic resistance.

Empowering Bacterial Self-Destruction

At the heart of their investigation lies Cap5, a pivotal protein within the CBASS system responsible for initiating bacterial cell suicide upon viral invasion. By unraveling the intricate interplay between Cap5 and cyclic nucleotides, the team uncovered a crucial dimer-to-tetramer transition triggered by the binding of second messengers. This transformative event propels Cap5 into an active state, facilitating the assembly of a tetramer and culminating in DNA destruction—a mechanism essential for curtailing viral spread within bacterial populations.

Translating Discoveries into Therapeutic Strategies

The study’s findings represent a paradigm shift in our understanding of bacterial defense mechanisms and offer a promising avenue for combating antibiotic-resistant infections. By harnessing the inherent self-destructive capabilities of bacteria, researchers envision a future where CBASS activation could serve as a potent strategy for managing bacterial infections.

Pioneering Structural Insights

Central to the research’s success was the innovative use of micro-focused synchrotron X-ray radiation, facilitated by Dale F. Kreitler, Ph.D., at Brookhaven National Laboratory. This advanced imaging technique enabled the visualization of Cap5’s structure in complex with cyclic nucleotides, unraveling the molecular underpinnings of CBASS activation.

Looking Ahead

As the battle against antibiotic resistance rages on, the researchers remain committed to exploring the broader implications of their discoveries across diverse bacterial species. With further investigations underway, including assessments of the approach’s efficacy against various pathogens, the study heralds a new era in the fight against infectious diseases.

Contributing to the Fight Against Superbugs

With antibiotic-resistant infections posing a significant threat to public health, the study’s findings hold profound implications for addressing this global challenge. By expanding the arsenal of antimicrobial strategies, researchers aim to stay one step ahead of evolving drug resistance and safeguard the health and well-being of populations worldwide.

Authors and Collaborators

The research was a collaborative effort involving contributions from Angeliki Buku, Ph.D., and Jithesh Kottur, Ph.D., alongside expert guidance from Daniela Sciaky, Ph.D. Together, their interdisciplinary approach paved the way for groundbreaking insights into bacterial defense mechanisms and their potential therapeutic applications.

More information: Olga Rechkoblit et al, Activation of CBASS Cap5 endonuclease immune effector by cyclic nucleotides, Nature Structural & Molecular Biology (2024). DOI: 10.1038/s41594-024-01220-x