An essential role for DNA adenine methylation in bacterial virulence

Salmonella typhimurium lacking DNA adenine methylase (Dam) were fully profi cient in colonization of mucosal sites but showed severe defects in coloniz ation of deeper tissue sites. These Dam(-) mutants were totally avirulent a nd were effective as live vaccines against murine typhoid fever. Dam regula ted the expression of at least 20 genes known to be induced during infectio n; a subset of these genes are among those activated by the PhoP global vir ulence regulator. PhoP, in turn, affected Dam methylation at specific genom ic sites, as Evidenced by alterations in DNA methylation patterns. Dam inhi bitors are likely to have broad antimicrobial action, and Dam- derivatives of these pathogens may serve as Live attenuated vaccines.