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.

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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 of 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,” said Dr. Levy. “The potential for these toxins to serve as a foundation for new clinical treatments or biotechnological innovations is particularly exciting.”

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.

 

The research paper titled “Systematic Discovery of Antibacterial and Antifungal Bacterial Toxins” is now available at Nature Microbiology and can be accessed at https://www.nature.com/articles/s41564-024-01820-9

DOI 10.1038/s41564-024-01820-9

 

Title: 50 Ways to Kill your Microbe

Credit: Yaara Oppenheimer-Shaanan

 

 

Description: E. coli bacteria exposed to production of each of the nine different new toxins (PT1-PT9) for 40 minutes showing different cell defects demonstrating different bacterial killing mechanisms. Fluorescent microscope images are shown with staining of DNA (blue), membrane (green) or an overlay of DNA and membrane staining. Scale bar: 2 µm. Arrows point to abnormal cells. Ctr: Normal untreated E. coli cells. PT1^Em led to DNA degradation. PT2^Nm led to elongated cells that cannot divide. PT3^Rs led to DNA leakage from cells. PT4^Ka led to membrane disintegration and swollen cells. PT5^Rb led to cell aggregation. PT6^Mc led to elongated cells. PT7^Bc led to DNA disappearance and membrane movement to the poles. PT8^Li: abnormal shaped E. coli and DNA degradation. PT9^Cn led to minichromosomes.

 

Researchers:

Nimrod Nachmias¹, Noam Dotan¹, Marina Campos Rocha², Rina Fraenkel³, Katharina Detert⁴, Monika Kluzek⁵, Maor Shalom¹, Shani Cheskis¹, Sonu Peedikayil-Kurien^6,7, Gilad Meitav¹, Arbel Rivitz¹, Naama Shamash-Halevy¹, Inbar Cahana³, Noam Deouell³, Jacob Klein⁵, Meital Oren-Suissa^6,7, Herbert Schmidt⁴, Neta Schlezinger², Netanel Tzarum³, Yaara Oppenheimer-Shaanan¹, and Asaf Levy¹

Institution:

1) The Department of Plant Pathology and Microbiology, The Institute of Environmental Science, The Robert H. Smith Faculty of Agriculture, Food, and Environment, The Hebrew University of Jerusalem

2) Koret School of Veterinary Medicine, The Robert H. Smith Faculty of Agricultural, Food & Environment, The Hebrew University of Jerusalem

3) The Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences,

Faculty of Mathematics & Science, The Hebrew University of Jerusalem

4) Institute of Food Science and Biotechnology, Department of Food Microbiology, University of Hohenheim, Stuttgart, Germany

5) Department of Materials and Interfaces, Weizmann Institute of Science

6) Department of Brain Sciences, Weizmann Institute of Science

7) Department of Molecular Neuroscience, Weizmann Institute of Science

 

The Hebrew University of Jerusalem is Israel’s premier academic and research institution. With over 23,000 students from 90 countries, it is a hub for advancing scientific knowledge and holds a significant role in Israel’s civilian scientific research output, accounting for nearly 40% of it and has registered over 11,000 patents. The university’s faculty and alumni have earned eight Nobel Prizes, two Turing Awards a Fields Medal, underscoring their contributions to ground-breaking discoveries. In the global arena, the Hebrew University ranks 81st according to the Shanghai Ranking. To learn more about the university’s academic programs, research initiatives, and achievements, visit the official website at http://new.huji.ac.il/en