Adaptive evolution of virulence and persistence in carbapenem-resistant Klebsiella pneumoniae

Among the most urgent public health threats is the worldwide emergence of carbapenem-resistant Enterobacteriaceae 1 – 4 , which are resistant to the antibiotic class of ‘last resort’. In the United States and Europe, carbapenem-resistant strains of the Klebsiella pneumoniae ST258 (ref. 5 ) sequence type are dominant, endemic 6 – 8 and associated with high mortality 6 , 9 , 10 . We report the global evolution of pathogenicity in carbapenem-resistant K. pneumoniae , resulting in the repeated convergence of virulence and carbapenem resistance in the United States and Europe, dating back to as early as 2009. We demonstrate that K. pneumoniae can enhance its pathogenicity by adopting two opposing infection programs through easily acquired gain- and loss-of-function mutations. Single-nucleotide polymorphisms in the capsule biosynthesis gene wzc lead to hypercapsule production, which confers phagocytosis resistance, enhanced dissemination and increased mortality in animal models. In contrast, mutations disrupting capsule biosynthesis genes impair capsule production, which enhances epithelial cell invasion, in vitro biofilm formation and persistence in urinary tract infections. These two types of capsule mutants have emerged repeatedly and independently in Europe and the United States, with hypercapsule mutants associated with bloodstream infections and capsule-deficient mutants associated with urinary tract infections. In the latter case, drug-tolerant K. pneumoniae can persist to yield potentially untreatable, persistent infection.