How bacteria share genes and defy defenses

A new study from Tel Aviv University has uncovered how bacterial defense mechanisms can be neutralized, facilitating more efficient genetic material transfer between bacteria. 

Researchers believe this discovery could significantly aid in combating antibiotic resistance and advancing genetic engineering for medical, industrial, and environmental applications.

The study was conducted by PhD student Bruria Samuel, under the guidance of professor David Burstein at the Shmunis School of Biomedicine and Cancer Research at Tel Aviv University‘s Wise Faculty of Life Sciences. 

The study also involved contributions from Dr. Karin Mittelman, Shirly Croitoru, and Maya Ben-Haim – all members of Burstein’s lab.

The role of DNA transfer in bacteria survival

Genetic diversity is critical for organisms to adapt and survive in changing environments. While humans and many other species achieve this through sexual reproduction, bacteria rely on alternative mechanisms. 

One key method is the direct transfer of DNA between cells, a process that enables rapid genetic exchange and adaptation. This mechanism is exemplified by the swift spread of antibiotic resistance among bacterial populations.

Despite its prevalence, the process of DNA transfer has remained somewhat mysterious. Bacteria possess sophisticated defense systems designed to destroy foreign DNA, raising the question: How do plasmids, the carriers of genetic material, evade these defenses?

Investigating conjugation and plasmid behavior

The study focused on conjugation, a primary mechanism for DNA transfer in bacteria. During this process, a bacterium connects to another via a microscopic tube, through which genetic material called plasmids is passed. 

“Plasmids are small, circular, double-stranded DNA molecules classified as ‘mobile genetic elements.’ Like viruses, plasmids move from one cell to another, but unlike viruses, they do not need to kill the host bacterium to complete the transfer,” explained Burstein.

Since plasmids are technically foreign DNA, they must find ways to evade bacterial defenses to survive and replicate within cells. 

Genes associated with anti-defense systems

Samuel began her research by analyzing 33,000 plasmids, identifying genes associated with anti-defense systems that allow plasmids to bypass bacterial defenses. The location of these genes proved to be a crucial discovery.

“The genes for the anti-defense systems that I identified were found to be concentrated near that cutting point, and organized in such a manner that they would be the first genes to enter the new cell,” noted Samuel. 

“This strategic positioning allows the genes to be activated immediately upon transfer, giving the plasmid the advantage needed to neutralize the recipient bacteria’s defense systems.”

When Samuel first presented her findings, Burstein admitted that he found it “hard to believe that such a phenomenon had not been identified before.” After an extensive review of the scientific literature, they confirmed that no prior studies had observed this pattern.

Plasmids evading defense systems

To test the computational findings, the team conducted laboratory experiments. They introduced antibiotic-resistant plasmids into bacteria equipped with CRISPR, a well-known bacterial defense system. 

This setup allowed the researchers to observe whether the plasmids could evade CRISPR and confer antibiotic resistance to the recipient bacteria.

Samuel’s experiments demonstrated that plasmids with anti-defense genes positioned near the DNA entry point successfully overcame the CRISPR system, enabling the bacteria to develop resistance. 

Conversely, plasmids with anti-defense genes located elsewhere were destroyed, and the bacteria succumbed to antibiotics.

Implications for antibiotic resistance 

Understanding the strategic positioning of anti-defense genes could lead to the discovery of new anti-defense systems, a topic of active research.

The findings may also enhance the design of plasmids for genetic manipulation in industrial and research settings.

“Our study can contribute to designing more efficient plasmids for genetic manipulation of bacteria in industrial processes,” said Burstein.

“While plasmids are already widely used for these purposes, the efficiency of plasmid-based genetic transfer in lab conditions is significantly lower than that of natural plasmids.”

Potential applications include designing plasmids to block antibiotic resistance genes in hospitals, enabling bacteria in soil and water to degrade pollutants, or improving human health by modifying gut bacteria.

Major breakthrough in biotechnology 

The study has been described as a major breakthrough in biotechnology. Dr. Ronen Kreizman, CEO of Ramot, Tel Aviv University’s technology transfer company, highlighted its potential. 

“The new research opens revolutionary possibilities in areas such as developing drugs against resistant bacteria, synthetic biology, agritech, and foodtech,” said Dr. Kreizman.

“The ability to control and fine-tune genetic material transfer between bacteria could become a powerful tool for addressing environmental, agricultural, and medical challenges.”

By unveiling the mechanisms that allow plasmids to overcome bacterial defenses, this research sets the stage for innovative solutions to pressing global challenges, including antibiotic resistance and environmental sustainability.

The study is published in the journal Nature.

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