Metabolic specialization drives reduced pathogenicity in Pseudomonas aeruginosa CF clinical isolates

Metabolism provides the foundation for all cellular functions. During persistent infections, in adapted pathogenic bacteria it functions radically differently compared with more naïve strains. However, whether this is simply a necessary accommodation to the persistence phenotype or if metabolism plays a direct role in achieving persistence in the host is still unclear. Here, we characterize a shift in metabolic functions aligned with a persistence phenotype occurring in eight infection scenarios of Pseudomonas aeruginosa colonization of people with cystic fibrosis. We identify clinical mutations in the key metabolic enzyme pyruvate dehydrogenase leading to a host specialized metabolism together with a lower virulence and immune response recruitment. This is mediated by impaired type III secretion system activity and by secretion of the antioxidant metabolite, pyruvate. These results provide evidence for the direct adaptiveness of metabolism during a persistent infection and its intrinsic role in supporting pathogenicity. ### Competing Interest Statement The authors have declared no competing interest.