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.