complete genome sequences of three clinical L. pneumophila isolates in 2004 paved the way for the understanding of the molecular biology of L. pneumophila in particular and Legionella in general. In-depth comparative genome analysis using DNA arrays to study the gene content of 180 Legionella strains revealed high genome plasticity and frequent horizontal gene transfer. Further insight in the L. pneumophila lifecycle was gained by investigating the gene expression profile of L. pneumophila in Acanthamoeba castellanii, its natural host. L. pneumophila exhibits a biphasic lifecycle and defines transmissive and replicative traits according to gene expression profiles. Genetic transformation Transformation is a bacterial adaptation involving the transfer of DNA from one bacterium to another through the surrounding liquid medium. Transformation is a bacterial form of sexual reproduction. In order for a bacterium to bind, take up, and recombine exogenous DNA into its chromosome, it must enter a special physiological state referred to as "competence". To determine which molecules may induce competence in L. pneumophila, 64 toxic molecules were tested. Only six of these molecules, all DNA-damaging agents, caused strong induction of competence. These were mitomycin C (which introduces DNA inter-strand crosslinks), norfloxacin, ofloxacin, and nalidixic acid (inhibitors of DNA gyrase that cause double-strand breaks), bicyclomycin (causes double-strand breaks), and hydroxyurea (causes oxidation of DNA bases). These results suggest that competence for transformation in L. pneumophilia evolved as a response to DNA damage. Perhaps induction of competence provides a survival advantage in a natural host, as occurs with other pathogenic bacteria. Drug Targets Several enzymes in the bacteria have been proposed as tentative drug targets. For example, enzymes in the iron uptake pathway have been suggested as important drug targets. Further, a cN-II class of IMP/GMP specific 5´-nucleotidase which has been extensively characterized kinetically. The tetrameric enzyme shows aspects of positive homotropic cooperativity, substrate activation and presents a unique allosteric site that can be targeted to design effective drugs against the enzyme and thus, the organism. Moreover, the enzyme is distinct than its human counterpart making it an attractive target for drug development. Treatment Macrolides (azithromycin or clarithromycin) or fluoroquinolones (levofloxacin or moxifloxacin) are the standard treatment for Legionella pneumonia in humans, with levofloxacin being considered first line with increasing resistance to azithromycin. Two studies support superiority of levofloxacin over macrolides, although not FDA approved. References External links Major topic "Legionella pneumophila": free-full text articles in PubMed Legionella pneumophila, causative agent of