Digital Insights Into Nucleotide Metabolism and Antibiotic Treatment Failure

Abstract

Nucleotide metabolism plays a central role in bacterial physiology, producing the nucleic acids necessary for DNA replication and RNA transcription. Recent studies demonstrate that nucleotide metabolism also proactively contributes to antibiotic-induced lethality in bacterial pathogens and that disruptions to nucleotide metabolism contributes to antibiotic treatment failure in the clinic. As antimicrobial resistance continues to grow unchecked, new approaches are needed to study the molecular mechanisms responsible for antibiotic efficacy. Here we review emerging technologies poised to transform understanding into why antibiotics may fail in the clinic. We discuss how these technologies led to the discovery that nucleotide metabolism regulates antibiotic drug responses and why these are relevant to human infections. We highlight opportunities for how studies into nucleotide metabolism may enhance understanding of antibiotic failure mechanisms.

Keywords: antibiotic persistence; antibiotic resistance; antibiotic tolerance; machine learning; metabolic modeling; nucleotide metabolism; predictive modeling; whole genome sequencing.

Figure 1

Recent innovations in interpretable machine learning for studying antibiotic treatment failure. (A) A biochemical screen was combined with metabolic network modeling and machine learning regression analyses to elucidate pathway mechanisms of antibiotic lethality. This led to the discovery that purine biosynthesis is a critical component of bactericidal antibiotic lethality (9). (B) Whole-genome sequencing data from antibiotic resistant (R) and susceptible (S) strains from clinical strains were applied as modeling constraints to genome-scale metabolic models. Machine learning classification analyses were applied (10).

Figure 2

Nucleotide metabolism is energetically expensive. De novo biosynthesis of purines (red) and pyrimidines (blue) begins with the pentose phosphate pathway (green), which generates phosphoribosyl pyrophosphate (prpp) from glycolysis (black). The energetic demand for ATP molecules to power purine and pyrimidine biosynthesis drives activity through the tricarboxylic acid (TCA) cycle (black) and oxidative phosphorylation (purple).

Figure 3

Nucleotide metabolism contributes to antibiotic lethality. In addition to their target-specific effects, bactericidal antibiotics induce purine biosynthesis, which increases activity in central metabolism. Increases in central metabolism stimulate the production of toxic reactive oxygen species, which oxidize nucleotides and damage DNA. These insults to DNA and the nucleotide pool induce bacterial death and may further potentiate purine biosynthesis.