Discovery of new bacterial toxins opens path to novel infection treatments

The Hebrew University of JerusalemOct 22 2024

Researchers have discovered a new group of bacterial toxins that can kill harmful bacteria and fungi, opening the door to potential new treatments for infections. These toxins, found in over 100,000 microbial genomes, can destroy the cells of bacteria and fungi without harming other organisms. The study revealed how some bacteria use these toxins to compete with other microbes, and the findings could lead to new ways to fight infections, especially as antibiotic resistance becomes a growing concern.

A new study, published in Nature Microbiology, led by Hebrew University researchers Dr. Asaf Levy from the Institute of Environmental Science, Dr. Neta Schlezinger from the Koret School of Veterinary Medicine and Dr. Netanel Tzarum from the Institute of Life Sciences in collaboration with Weizmann Institute of Science researchers Profs. Jacob Klein and Meital Oren-Suissa, and with Prof. Herbert Schmidt from University of Hohenheim, has revealed a new arsenal of bacterial toxins with the potential to fight infectious human and plant diseases. These toxins, which are encoded in the genomes of certain bacteria, exhibit potent antibacterial and antifungal properties, offering exciting new possibilities for clinical and biotechnological applications.

Microbial competition is a natural phenomenon, and bacteria have evolved sophisticated methods, including toxins, to eliminate competitors. The most famous examples of natural compounds used in competition in nature are antibiotics produced by bacteria and fungi.

In this study, Dr. Levy's team developed an innovative computational approach to identify previously undiscovered toxin protein domains, which are 100-150 amino acid long, within over 105,000 microbial genomes. These protein toxins, referred to as polymorphic toxins, play a crucial role in microbial warfare, targeting and killing competing microorganisms in different ecosystems.

The research team, students and postdoctoral fellows: Nimrod Nachmias, Noam Dotan, and Dr. Marina Campos Rocha, and staff scientists Dr. Yaara Oppenheimer-Shaanan and Rina Fraenkel, successfully validated nine newly discovered toxins, each representing a large evolutionary conserved family, demonstrating their ability to cause cell death in both Escherichia coli and Saccharomyces cerevisiae when expressed in these model organisms. Of particular note, five antitoxin genes, also known as immunity genes, were also identified, which protect the bacteria producing the toxins from self-destruction.

Interesting to note that the toxins exhibit powerful antifungal activity against a range of pathogenic fungi, while leaving certain invertebrate species and macrophages unaffected. The study's experimental results suggest that these toxins primarily act as efficient enzymes that target essential cellular processes, such as the cell membrane, DNA, or cell division. Structural analysis of two toxin-immunity protein complexes further confirmed that some of these toxins possess DNase activity, which can degrade DNA in target cells. Interestingly, the structure show that the toxin is positively charged in its DNA binding site, to bind the negatively charged DNA, whereas the antitoxin protein is negatively charged to prevent the toxin from binding to the target DNA.

Our findings expand our understanding of how bacteria use toxins in competition with other microbes and provide exciting avenues for future research into critically needed antimicrobial agents against human and plant bacterial and fungal pathogens. The potential for these toxins to serve as a foundation for new clinical treatments or biotechnological innovations is particularly exciting."

Dr. Asaf Levy, Institute of Environmental Science, Hebrew University

This research not only enhances the knowledge of microbial toxins but also sheds light on their potential therapeutic use. The team's discovery could pave the way for novel antimicrobial strategies, particularly as the world grapples with the rise of antibiotic-resistant pathogens.

The study has broad implications for both the understanding of microbial interactions in different environments and the development of next-generation antimicrobials. By revealing the mechanisms through which these toxins operate, the research offers hope for new treatments in the ongoing fight against bacterial and fungal infections.