ABSTRACT
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
ABSTRACT
Among the most urgent public health threats is the worldwide emergence of carbapenem-resistant Enterobacteriaceae1-4, 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, endemic6-8 and associated with high mortality6,9,10. 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.
Subject(s)
Adaptation, Biological/genetics , Carbapenem-Resistant Enterobacteriaceae/genetics , Evolution, Molecular , Klebsiella pneumoniae/genetics , Virulence/genetics , beta-Lactam Resistance/genetics , Adult , Animals , Bacterial Capsules/genetics , Carbapenem-Resistant Enterobacteriaceae/classification , Carbapenem-Resistant Enterobacteriaceae/isolation & purification , Carbapenem-Resistant Enterobacteriaceae/pathogenicity , Carbapenems/therapeutic use , Cells, Cultured , Female , Genome, Bacterial , Humans , Klebsiella Infections/microbiology , Klebsiella Infections/urine , Klebsiella pneumoniae/classification , Klebsiella pneumoniae/isolation & purification , Klebsiella pneumoniae/pathogenicity , Mice , Mice, Inbred BALB C , Mice, Inbred C3H , Mice, Transgenic , Phylogeny , Polymorphism, Single Nucleotide , Urinary Tract Infections/microbiology , Urinary Tract Infections/urine , ZebrafishABSTRACT
Compartmentalization of metabolism into specific regions of the cell, tissue, and organ is critical to life for all organisms. Mass spectrometric imaging techniques have been valuable in identifying and quantifying concentrations of metabolites in specific locations of cells and tissues, but a true understanding of metabolism requires measurement of metabolite flux on a spatially resolved basis. Here, we utilize desorption ESI-MS (DESI-MS) to measure lipid turnover in the brains of mice. We show that anatomically distinct regions of the brain have distinct lipid turnover rates. These turnover measurements, in conjunction with relative concentration, will enable calculation of regiospecific synthesis rates for individual lipid species in vivo. Monitoring spatially dependent changes in metabolism has the potential to significantly facilitate research in many areas, such as brain development, cancer, and neurodegeneration.
