Flexible Metabolism and Suppression of Latent Enzymes Are Important for Adaptation to Diverse Environments within the Host.

Bacterial metabolism is necessary for adaptation to the host microenvironment. Flexible metabolic pathways allow uropathogenic (UPEC) to harmlessly reside in the human intestinal tract and cause disease upon extraintestinal colonization. intestinal colonization requires carbohydrates as a carbon source, while UPEC extraintestinal colonization requires gluconeogenesis and the tricarboxylic acid cycle. UPEC containing disruptions in two irreversible glycolytic steps involving 6-carbon (6-phosphofructokinase; ) and 3-carbon (pyruvate kinase; ) substrates have no fitness defect during urinary tract infection (UTI); however, both reactions are catalyzed by isozymes: 6-phosphofructokinases Pfk1 and Pfk2, encoded by and , and pyruvate kinases Pyk II and Pyk I, encoded by and UPEC strains lacking one or both phosphofructokinase-encoding genes ( and ) and strains lacking one or both pyruvate kinase genes ( and ) were investigated to determine their regulatory roles in carbon flow during glycolysis by examining their fitness during UTI and growth requirements. Loss of a single phosphofructokinase-encoding gene has no effect on fitness, while the double mutant outcompeted the parental strain in the bladder. A defect in bladder and kidney colonization was observed with loss of , while loss of resulted in a fitness advantage. The mutant was indistinguishable from wild-type , suggesting that the presence of Pyk II rather than the loss of Pyk I itself is responsible for the fitness defect in the mutant. These findings suggest that suppresses latent enzymes to survive in the host urinary tract. Urinary tract infections are the most frequently diagnosed urologic disease, with uropathogenic (UPEC) infections placing a significant financial burden on the health care system by generating more than two billion dollars in annual costs. This, in combination with steadily increasing antibiotic resistances to present day treatments, necessitates the discovery of new antimicrobial agents to combat these infections. By broadening our scope beyond the study of virulence properties and investigating bacterial physiology and metabolism, we gain a better understanding of how pathogens use nutrients and compete within host microenvironments, enabling us to cultivate new therapeutics to exploit and target pathogen growth requirements in a specific host environment.