A global team has made significant progress in understanding how bacterial plasmids contribute to antibiotic resistance.

Their findings reveal a complex mechanism involving KorB and KorA proteins, which could lead to innovative therapies that weaken drug-resistant bacteria.

A breakthrough in the study of bacterial resistance

An international team of researchers has made a major breakthrough in understanding how bacteria develop resistance to antibiotics.

Bacteria use a variety of defense mechanisms to protect themselves from antibiotics, a growing global public health challenge.

A key defense mechanism involves plasmids, small DNA molecules inside bacterial cells. These plasmids have their own genetic material and can carry genes that make bacteria resistant to antibiotics.

By revealing the specific role plasmids play in bacterial resistance, scientists can develop new therapies aimed at fighting drug-resistant infections more effectively.

揭示KorB-KorA機制

Researchers and partners at the John Innes Center used a model plasmid called RK2, which is used globally to study clinically relevant plasmids that spread antimicrobial resistance.

They initially focused on a molecule called KorB, which is essential for plasmids to survive in the bacterial host. This DNA-binding protein was previously thought to play a role in controlling gene expression, but how this happens is unclear.

To solve this problem, they worked with top experts from Madrid, New York, and Birmingham, England.

Implications for future treatments

Using advanced microscopy and protein crystallography techniques, the team discovered that KorB interacts with another molecule called KorA. The KorB-KorA regulatory system shuts down bacterial gene expression, with KorB acting as a DNA slide clamp and KorA acting as a lock, holding KorB in place.

Together, this complex shuts down gene expression to keep the plasmid safe within its bacterial host.

This newly discovered mechanism provides a new perspective for studying remote gene silencing in bacteria. This is a phenomenon in which regulatory components such as the KorB-KorA complex interact with distant target genes, in which case they are turned off, allowing the plasmid to survive in the bacterial host.

The study's first author, Dr. Thomas McLean, a postdoctoral fellow at the John Innes Center, said the discovery was a triumph for curiosity-driven science: "Initially the focus of this project was on KorB. Then there was a lucky "Friday afternoon" experiment, which was purely out of curiosity and focused our attention on KorA's ability to clamp KorB in the right place at the right time. This was a huge breakthrough that completely changed the direction of the project. Our study provides a new paradigm for remote gene regulation in bacteria and a target for new therapeutics to destabilize host plasmids and re-sensitize them to antibiotics. ”

This study solves a decades-long puzzle in the field about how KorB, a key protein in the multidrug-resistant plasmid RK2 in bacteria, controls the opening and closing of genes.

This study is being expanded to include more clinically relevant plasmids and further explore the KorB-KorA mechanism to understand how it breaks down at the right time.

KorB switched from DNA slide clamp to repressor mediated remote gene silencing in multidrug-resistant plasmids, a study published in Nature Microbiology.