An international team has made significant progress in uncovering the genetic processes that enable bacteria to resist drugs.
An international team has made significant progress in uncovering the genetic processes that enable bacteria to resist drugs.
Bacteria possess various protective strategies to develop resistance against antibiotics, a major concern for public health worldwide.
One of these strategies involves plasmids, which are small DNA fragments found in bacterial cells. These plasmids have their own distinct genome and carry the ability to resist antibiotics.
By understanding the functions of plasmids in bacteria, we can harness this knowledge to devise a new class of treatments targeting drug-resistant infections.
Researchers at the John Innes Centre collaborated with partners using a plasmid called RK2, which is commonly used to study clinically significant plasmids that confer antimicrobial resistance.
Their initial investigation centered on a molecule named KorB, essential for the preservation of plasmids within their bacterial hosts. While it was already known that this DNA-binding protein influenced gene expression, the specifics of its role remained unclear.
To gain clarity on this, they partnered with experts from Madrid, New York, and Birmingham, UK.
Employing cutting-edge microscopy and protein crystallography, the team found that KorB interacts with another molecule named KorA. This KorB-KorA regulatory module effectively halts gene expression in bacteria, with KorB acting like a clamp that slides along the DNA, while KorA functions as a lock securing KorB in position.
Together, this system effectively prevents gene expression, ensuring the plasmid remains intact within its bacterial host.
This newly identified mechanism provides new insights into long-range gene silencing in bacteria, allowing regulatory elements like the KorB-KorA complex to interact with distant target genes, turning them off to aid plasmid survival.
Dr. Thomas McLean, the lead author of the study and a postdoctoral researcher at the John Innes Centre, describes the discovery as a triumph of exploratory science: “Initially, our project concentrated on KorB. A fortunate ‘Friday afternoon’ experiment, driven purely by curiosity, directed our attention to how KorA can secure KorB precisely when needed. This was an immense breakthrough that completely shifted our project’s focus. Our findings establish a new framework for understanding bacterial long-range gene regulation and present a target for innovative therapies that could destabilize plasmids in their hosts, making them more sensitive to antibiotics.”
This research addresses a longstanding puzzle regarding how the key protein KorB regulates the activation and deactivation of genes in the multi-drug-resistant plasmid RK2 in bacteria.
The investigation will continue to delve into other clinically significant plasmids and explore the KorB-KorA mechanism to understand how it disassembles at the appropriate moment.
The paper titled “KorB switching from DNA-sliding clamp to repressor mediates long-range gene silencing in a multi-drug resistance plasmid” is published in Nature Microbiology.
