DNA defense systems become a fitness liability during plasmid conjugation.

Conjugative plasmid transfer via lethal zygosis selectively reduces the fitness of non-permissive Escherichia coli recipients, with repeated T4SS engagement damaging cells that fail to establish RK2.

• Why it matters: Antibiotic-free persistence and spread of conjugative plasmids remain uncertain, especially how plasmids exploit or overcome bacterial DNA defenses without external selection.
• What they did: The study used contact-dependent antagonism and blocked RK2 establishment with CRISPR-Cas or restriction-modification, then built transposon vectors co-delivering exclusion genes to boost editing.
• The result: Blocking plasmid establishment caused strong fitness defects in Escherichia coli by preventing exclusion gene expression, and co-delivering exclusion genes increased gene editing efficiency by orders of magnitude.

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