Sugar-Phosphate Toxicities Attenuate Salmonella Fitness in the Gut

• Published in: Journal of bacteriology 2022-12, Vol.204 (12), p.e0034422
• Main Authors: Boulanger, Erin F, Sabag-Daigle, Anice, Baniasad, Maryam, Kokkinias, Katherine, Schwieters, Andrew, Wrighton, Kelly C, Wysocki, Vicki H, Ahmer, Brian M M
• Format: Article
• Language: English
• Subjects: Accumulation; Animals; Antimicrobial agents; Bacteria; Bacteriology; Catabolism; Defects; Drinking water; Drinking Water - metabolism; Fitness; Genes; Humans; Infections; Mice; Mutants; Mutation; Nutrient availability; Pathogens; Phosphates - metabolism; Reproductive fitness; Research Article; Salmonella; Salmonella - genetics; Salmonella enterica - genetics; Sugar; Sugars - metabolism; Therapeutic targets; Toxicity
• ISSN: 0021-9193; 1098-5530
• DOI: 10.1128/jb.00344-22

Pathogens are becoming resistant to antimicrobials at an increasing rate, and novel therapeutic strategies are needed. Using Salmonella as a model, we have investigated the induction of sugar-phosphate toxicity as a potential therapeutic modality. The approach entails providing a nutrient while blocking the catabolism of that nutrient, resulting in the accumulation of a toxic intermediate. We hypothesize that this build-up will decrease the fitness of the organism during infection given nutrient availability. We tested this hypothesis using mutants lacking one of seven genes whose mutation is expected to cause the accumulation of a toxic metabolic intermediate. The , , , , , , and mutants were then provided the appropriate sugars, either or during gastrointestinal infection of mice. All but the mutant had nutrient-dependent growth defects , suggestive of sugar-phosphate toxicity. During gastrointestinal infection of mice, five mutants had decreased fitness. Providing the appropriate nutrient in the animal's drinking water was required to cause fitness defects with the and mutants and to enhance the fitness defect of the mutant. The and mutants were severely attenuated regardless of the nutrient being provided in the drinking water. Homologs of are widespread among bacteria and in humans, rendering the specific targeting of bacterial pathogens difficult. However, the , , and genes are not present in humans, appear to be rare in most phyla of bacteria, and are common in several genera of , making the encoded enzymes potential narrow-spectrum therapeutic targets. Bacterial pathogens are becoming increasingly resistant to antibiotics. There is an urgent need to identify novel drug targets and therapeutic strategies. In this work we have assembled and characterized a collection of mutations in our model pathogen, Salmonella enterica, that block a variety of sugar utilization pathways in such a way as to cause the accumulation of a toxic sugar-phosphate. Mutations in three genes, , , and , dramatically decrease the fitness of Salmonella in a mouse model of gastroenteritis, suggesting that RhaD, AraD, and MtlD may be good narrow-spectrum drug targets. The induction of sugar-phosphate toxicities may be a therapeutic strategy that is broadly relevant to other bacterial and fungal pathogens.