Unlocking the Passcodes to Manipulate Natural Bacterial Communities

Analysis of bacterial toxin-antitoxin systems sheds new light on how microbes interact with other members of their communities.

The Science

Bacteria commonly produce toxins that are lethal to themselves. These bacteria can gain temporary protection by also producing antitoxins, but the bacteria die if they stop making antitoxins. Why would bacteria put themselves in danger? If scientists can learn the rules, they may be able to take advantage of bacterial warfare. Researchers have studied these toxin-antitoxin (TA) systems for more than 40 years but have struggled to capitalize on them because they vary unpredictably, even within species of bacteria. Now, by studying bacterial communities instead of individual species, scientists have uncovered a natural order to TA systems. This result makes the behavior and use of these TA systems more predictable.

The Impact

Interactions between members of natural microbial communities are hard to decode. However, to develop biotechnology solutions, scientists need an understanding of how microbes cooperate or compete. A common interaction within bacterial communities is the exchange of DNA. Often, the exchanged DNA contains TA systems, which play an important role in how bacteria interact. TA systems are particularly persistent because the bacteria in a community that lose these systems die. This means that over time, members of a community develop a shared set of TA systems. This acts like a membership passcode that controls who belongs. By engineering microbes with the right “passcodes,” scientists can grant or prevent entry into targeted natural communities. This opens new ways to precisely manipulate community membership without relying on traditional antibiotics that kill microbes in a community indiscriminately.

Summary

Community context is essential to understanding bacterial life. Bacteria constantly exchange DNA with other bacteria in their communities. Unlike humans, who all share a nearly identical set of genes, individual strains of a bacterial species may have only 60% of their genes in common. They receive the rest of their genes from other microbes. This process, called horizontal gene transfer (HGT), creates a living DNA record of community interactions. Highly prevalent genes like TA systems, which cause or prevent death, are especially valuable clues to microbial behavior.

A team of researchers at Lawrence Livermore National Laboratory used a computational approach to build a similarity network of TA systems using a database of more than 10,000 bacterial plasmid sequences. Plasmids are small, circular DNA molecules that contain genes, including TA systems. The database includes information on the microbial community where each plasmid came from. Studying TA systems in the context of communities proved to be the key to understanding their spread. The researchers found that microbial communities have consistent and unique TA patterns, such that membership can be predicted with 95% accuracy from TA systems alone. This not only reduces the need to compare whole genomes for community identification, but also offers a more targeted way to manage bacteria at the community level than broad-spectrum antibiotics.

Contact

Funding

This work is supported by the Department of Energy Office of Science, Office of Biological and Environmental Research, and by the Lawrence Livermore National Laboratory BioSecure Scientific Focus Area within the Secure Biosystems Design program.

Publications

Bethke, J.H., Kimbrel, J., Jiao, Y., and Ricci, D., Toxin-antitoxin systems reflect community interactions through horizontal gene transfer. Molecular Biology and Evolution 41, 11 (2024). [DOI: 10.1093/molbev/msae206]

Highlight Categories

Program: BER , BSSD

Performer: DOE Laboratory