De novo or Salvage? Nucleotide Availability as a Driver of Bacterial Adaptation and Virulence

Bacterial pathogens rely on the constant availability of purine and pyrimidine nucleotides to facilitate replication, growth, and virulence and to sustain energy metabolism and nucleotide-based signaling. The capacity to switch between de novo synthesis and salvage pathways underpins much of their metabolic flexibility and also regulates access to different human body niches, where nucleobase availability varies significantly between extracellular fluids, mucosal surfaces, inflamed tissues, and intracellular compartments. However, adaptation to specific host niches can result in the loss of de novo nucleotide biosynthesis pathways, increasing bacterial dependence on nucleobase/nucleoside salvage. Many intracellular pathogens lack de novo synthesis pathways, making purine or pyrimidine salvage not an optional, but an essential process where host nucleotide reserves are critical to bacterial survival. Because of their central role in bacterial metabolism, enzymes, transporters, and regulatory networks involved in purine and pyrimidine metabolism represent potential targets for therapeutic interventions. This review summarizes the current knowledge of purine and pyrimidine metabolism in bacterial pathogens, including the abundance of these compounds in different host niches, tissue-specific fitness strategies, and bacterial targets for further development of innovative antibacterials.