Plasmids have an important role in driving bacterial evolution as they mobilize genes by horizontal gene transfer, including antibiotic resistance genes. Plasmid transfer via conjugation involves the assembly of the relaxosome protein complex and the nicking of the nic site located within the origin of transfer (oriT). The resulting single-stranded T-strand is transferred into the recipient cell, and the first transferred region is termed the leading region, whereas the region that enters the cell last is called the lagging region. Bacterial cells exhibit various defence systems against invading exogenous nucleic acids, but despite those systems, horizontal gene transfer is widespread in bacteria. It has been shown that genes in the leading region can be expressed early and that some encode genes essential for plasmid establishment. However, most of the genes within the region remain uncharacterized. Now, Burstein and colleagues show that the leading regions have a key role in overcoming host immunity by functioning as ‘anti-defence islands’ that protect the invading plasmid.

In addition to these anti-defence genes, the authors also identified DNA-methyltransferases (MTases) in this region, which might have a protective role against host restriction–modification systems. Additionally, they found toxin–antitoxin genes and single-stranded DNA-binding proteins (SSBs). SSBs have been shown to be important for effective SOS inhibition, prevention of single-stranded DNA degradation and might protect against CRISPR–Cas systems. Numerous uncharacterized genes were also represented in the leading region. The authors performed structural analyses of these uncharacterized proteins and uncovered additional potential anti-defence proteins, which further highlights the prevalence of such systems in the leading region.