P112: Withdrawn: Exploring the Secondary Metabolome of the Human Pathogen Legionella pneumophila

Bacteria have evolved a complex secondary metabolism that serves to increase fitness in challenging environments through the production of bioactive metabolites. Bioactivity is often associated with requirements of specific environmental niches, as observed with insecticides from insect pathogens, and herbicides from plant pathogens. Studies indicate that human pathogens also use small molecules during infection, and that these compounds may be adapted for manipulating human systems. Among bacterial pathogens that manipulate host intracellular processes, Legionella pneumophila is perhaps the most adept, converting a hostile macrophage into a complacent food source within a few hours of infection. Genome inspection has revealed that Legionella possesses three biosynthetic gene clusters that may yield specific compounds to control intracellular events. Here, we demonstrate that Legionella pneumophila can produce novel secondary metabolites that influence host biology. Initially, a series of biosynthetically deficient strains were generated, and metabolomic analysis was used to reveal that a unique biosynthetic gene cluster produced a novel polyketide surfactant. Infection studies using macrophage cell lines indicated that a second gene cluster was involved in preventing phagosome-lysosome fusion, a crucial first step during intracellular infection. Our results demonstrate that human pathogens can produce novel small molecules to manipulate host cells during infection, and that these bacteria may be a valuable source of bioactive metabolites for use as probes of cell biology or for treating human diseases.