Metabolism and Fitness of Urinary Tract Pathogens

Adaptation of metabolism and basic physiology allows E. coli to replicate in diverse host microenvironments. ExPEC that cause urinary tract infection, bacteremia, sepsis, and meningitis, have adapted to grow as a harmless commensal in the nutrient-replete, carbon-rich human intestine but rapidly transition to pathogenic lifestyle in the nutritionally poor, nitrogen-rich urinary tract. In order to establish a commensal association within the human intestine, adaptive factors such as metabolic flexibility allow E. coli to successfully compete for carbon and energy sources with a large and diverse bacterial population. E. coli acquires nutrients from the intestinal mucus, including N-acetylglucosamine, sialic acid, glucosamine, gluconate, arabinose, fucose and simple sugars released upon breakdown of complex polysaccharides by anaerobic gut residents. When UPEC transition to the urinary tract, the bacteria encounter a drastic reduction in the abundance of nutrients and bacterial competition. Consequently, to replicate in a new host microenvironment, UPEC utilization of metabolic pathways required for growth in the dilute mixture of amino acids and peptides in the bladder signals the bacterium to elaborate virulence properties to successfully cause invasive disease and survive the onslaught of bactericidal host defenses. These adaptations are a unique and essential characteristic of ExPEC that enable a successful transition between disparate microenvironments within the same individual ( 13 ).

UPEC acquires amino acids and requires gluconeogenesis and the TCA cycle for fitness in vivo. Peptide substrate-binding protein genes dppA and oppA are required to import di- and oligopeptides into the cytoplasm from the periplasm. Short peptides are degraded into amino acids in the cytoplasm and converted into pyruvate and oxaloacetate. Pyruvate is converted into acetyl-CoA and enters the TCA cycle to replenish intermediates and generate oxaloacetate. Oxaloacetate is converted to phosphoenolpyruvate by the pckA gene product during gluconeogenesis. Mutations in the indicated genes dppA, oppA, pckA, sdhB, and tpiA demonstrated fitness defects in vivo. ( 18 )

Diagram of central metabolism and map of the specific pathways disrupted by targeted mutations in uropathogenic E. coli. Carbon sources or biochemical intermediates shared between pathways are indicated in capital letters or abbreviated: G6P, glucose-6-phosphate; F6P, fructose-6-phosphate; G3P, glyceraldehyde-3-phosphate; 6PGN, 6-phosphogluconate. Reactions are denoted with arrows. Specific reactions (red arrows) were targeted by deletion or insertion in E. coli CFT073. In glycolysis: pgi, glucose-6-phosphate isomerase; pfkA, 6-phosphofructokinase transferase; tpiA, triosephosphate isomerase; pykA, pyruvate kinase; in pentose phosphate pathway: gnd, 6-phosphogluconate dehydrogenase; talB, transaldolase; in Entner-Duodoroff pathway: edd, 6-phosphogluconate dehydratase; in gluconeogenesis: pckA, phosphoenolpyruvate carboxykinase; and in the TCA cycle: sdhB, succinate dehydrogenase; fumC, fumarate hydratase; frdA, fumarate reductase. ( 43 )

Model describing the C/N ratio within the urinary tract for E. coli. The urinary tract environment has a low C/N ratio due to the dilute mixture of amino acids and peptides as the primary carbon source and the abundance of urea in urine providing a substantial nitrogen contribution. E. coli is unable to utilize or sense the nitrogen sequestered in urea because it lacks urease, which liberates ammonia from urea. This results in E. coli activation of the glutamine synthetase and glutamate oxo-glutarate aminotransferase system (GS/GOGAT) to assimilate nitrogen. ( 43 )