A global team has made a significant advance in understanding how bacterial plasmids contribute to antibiotic resistance.
Their findings reveal a complex mechanism involving the proteins KorB and KorA, which could lead to innovative treatments to weaken drug-resistant bacteria.
Breakthrough in Bacterial Resistance Research
An international team of researchers has made a major breakthrough in understanding how bacteria develop resistance to antibiotics.
Bacteria use multiple defense mechanisms to protect themselves from antibiotics, which is a growing global public health challenge.
One key defense mechanism involves plasmids—small DNA molecules within bacterial cells. These plasmids have their own genetic material and can carry genes that make bacteria resistant to antibiotics.
By uncovering the specific roles plasmids play in bacterial resistance, scientists can develop new treatments aimed at combating drug-resistant infections more effectively.
Unveiling the KorB-KorA Mechanism
John Innes Centre researchers and partners used a model plasmid called RK2 that is used globally to study clinically relevant plasmids that transmit antimicrobial resistance.
Their initial focus was a molecule called KorB which is essential for plasmids to survive within their bacterial hosts. This DNA-binding protein was previously known to have played a role in controlling gene expression but how this happens was unclear.
To figure this out they teamed up with leading experts from Madrid, New York, and Birmingham, UK.
Implications for Future Therapeutics
Using advanced microscopy and protein crystallography techniques, the research team discovered that KorB interacts with another molecule called KorA. This KorB-KorA regulatory system shuts down bacterial gene expression, KorB acting as a DNA sliding clamp and KorA as a lock that holds KorB in place.
Together this complex shuts off gene expression to keep the plasmid safe within its bacterial host.
This newly discovered mechanism offers a fresh insight into long-range gene silencing in bacteria. This is the phenomenon by which regulatory elements such as the KorB-KorA complex can interact with distant target genes, in this case switching them off so that the plasmid can survive in the bacterial host.
First author of the study Dr. Thomas McLean, a postdoctoral researcher at the John Innes Centre, says the discovery is a triumph of curiosity-driven science: “Originally this project set out to focus on KorB. Then a lucky “Friday afternoon” experiment, which was done purely out of curiosity, brought our focus to the ability of KorA to clamp KorB in the right place at the right time. This was a huge breakthrough that drastically changed the direction of the project. Our study provides a new paradigm for bacterial long-range gene regulation and offers a target for novel therapeutics to destabilize plasmids in their host and re-sensitize them to antibiotics.”
The study solves a decades-long conundrum in the field, of how the critical protein KorB controls when genes are switched on and off in the multi-drug-resistant plasmid RK2 in bacteria.
The research is being expanded to include more clinically relevant plasmids and to probe further into the KorB-KorA mechanism to see how it disassembles at the correct time.
KorB switching from DNA-sliding clamp to repressor mediates long-range gene silencing in a multi-drug resistance plasmid is in Nature Microbiology.
Reference: “KorB switching from DNA-sliding clamp to repressor mediates long-range gene silencing in a multi-drug resistance plasmid” by Thomas C. McLean, Francisco Balaguer-Pérez, Joshua Chandanani, Christopher M. Thomas, Clara Aicart-Ramos, Sophia Burick, Paul Dominic B. Olinares, Giulia Gobbato, Julia E. A. Mundy, Brian T. Chait, David M. Lawson, Seth A. Darst, Elizabeth A. Campbell, Fernando Moreno-Herrero and Tung B. K. Le, 23 January 2025, Nature Microbiology.
DOI: 10.1038/s41564-024-01915-3
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1 Comment
wow. this is significant indeed.
I have psoriasis and when I take a biologic, I am very prone to bacterial infections .
if I understand correctly this would allow me to get rid of many diseases including psoriasis, chrons and any disease were a biologic treatment is necessary.