Antibiotic resistance is one of the most pressing health challenges of our time. The culprits
often hide in tiny circular DNA fragments called plasmids, which can jump between
bacteria and spread resistance genes like wildfire. But bacteria are not defenceless: they
possess their own immune systems to detect and destroy these genetic intruders. One of
the most intriguing of these systems is known as DdmDE, found in the bacterium Vibrio
cholerae, the pathogen behind cholera outbreaks. How this microscopic defence
mechanism distinguishes between self and enemy DNA, however, remains a mystery.
This project aims to uncover how the DdmDE system recognizes and eliminates invading
plasmids while leaving the bacteriums own DNA untouched. Understanding this self-
versus-non-self discrimination is essential to grasp how bacteria protect themselves and
control the spread of antibiotic resistance.
To do so, researchers will combine biochemical experiments, cryo-electron microscopy,
and live-cell fluorescence imaging to visualize DdmDE in action from its first contact
with foreign DNA to the complete destruction of a plasmid inside a living cell. This
integrated approach will reveal the molecular steps that activate DdmDE and allow it to
selectively degrade plasmids.
Beyond its biological importance, this project could open new avenues for biotechnology.
Systems like DdmDE represent a largely untapped source of programmable DNA-cutting
tools, potentially complementing or even improving on CRISPR technologies. By
decoding how bacteria achieve such precise DNA targeting, this research will not only
advance our understanding of microbial immunity but may also lay the groundwork for the
next generation of genome-editing methods.