The spread of antibiotic resistance is a major challenge for the treatment of bacterial infections. It is largely driven by horizontal gene transfer in certain bacteria, one of the main mechanisms being natural transformation: the bacterium captures DNA present in its environment and integrates it into its own genome through homologous recombination. This phenomenon plays a key role in bacterial evolution, enabling them to acquire antibiotic resistance or increased virulence.

During natural transformation, the integration of single-stranded DNA into a bacterial chromosome requires specific proteins. In Gram-negative bacteria, one of these key proteins is the helicase ComM. In a study published in PNAS, researchers from IRCM (CEA/UPSaclay, UP Cité, Fontenay-aux-Roses) and I2BC (CEA/CNRS/UPSaclay, Gif-sur-Yvette), in collaboration with a laboratory at Indiana University in the United States, demonstrated how this helicase is recruited during the process of natural transformation.

Guided by bioinformatic analyses, they showed that ComM directly interacts with another transformation-specific protein, DprA. In the molecular mechanism of natural transformation, DprA acts as a guide. It binds the incoming DNA fragment inside the bacterium and recruits the RecA protein, with which the transforming DNA is delivered to the recombination site on the bacterial chromosome. Using structural models generated with the AlphaFold tool, they proposed mutations to disrupt this interaction. The effect of these mutations on the efficiency of natural transformation shows that interaction with DprA is essential for ComM to fulfill its role in integrating exogenous DNA in two clinically important bacterial pathogens, Helicobacter pylori and Vibrio cholerae. In both bacteria, natural transformation is the primary mechanism of horizontal gene transfer. This study confirms the value of structural models for uncovering new protein–protein interactions and gaining a better understanding of the molecular mechanisms underlying the coordination of their activities.

The results of this study provide new insights into the process of natural transformation in Gram-negative bacteria and may have implications for combating the spread of antibiotic resistance. By targeting the interactions between DprA and ComM, it may be possible to develop new strategies to limit gene transfer between bacteria, particularly those involved in antibiotic resistance or virulence.

​​Contacts : jessica.andreani@cea.fr et pablo.radicella@cea.fr