2. Academic Validation
  3. A folate inhibitor exploits metabolic differences in Pseudomonas aeruginosa for narrow-spectrum targeting

A folate inhibitor exploits metabolic differences in Pseudomonas aeruginosa for narrow-spectrum targeting

  • Nat Microbiol. 2024 May;9(5):1207-1219. doi: 10.1038/s41564-024-01665-2.
Connor Chain 1,  Joseph P Sheehan 1,  Xincheng Xu 2 3,  Soodabeh Ghaffari 1,  Aneesh Godbole 4,  Hahn Kim 3 5,  Joel S Freundlich 4 6,  Joshua D Rabinowitz 2 3 7,  Zemer Gitai 8
Affiliations

Affiliations

  • 1 Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
  • 2 Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.
  • 3 Department of Chemistry, Princeton University, Princeton, NJ, USA.
  • 4 Department of Pharmacology, Physiology and Neuroscience, Rutgers University - New Jersey Medical School, Newark, NJ, USA.
  • 5 Small Molecule Screening Center, Princeton University, Princeton, NJ, USA.
  • 6 Division of Infectious Disease, Department of Medicine and the Ruy V. Lourenço Center for the Study of Emerging and Re-emerging Pathogens, Rutgers University - New Jersey Medical School, Newark, NJ, USA.
  • 7 Ludwig Institute for Cancer Research, Princeton Branch, Princeton University, Princeton, NJ, USA.
  • 8 Department of Molecular Biology, Princeton University, Princeton, NJ, USA. zgitai@princeton.edu.
PMID: 38594311 DOI: 10.1038/s41564-024-01665-2
Abstract

Pseudomonas aeruginosa is a leading cause of hospital-acquired infections for which the development of Antibiotics is urgently needed. Unlike most enteric bacteria, P. aeruginosa lacks Enzymes required to scavenge exogenous thymine. An appealing strategy to selectively target P. aeruginosa is to disrupt thymidine synthesis while providing exogenous thymine. However, known Antibiotics that perturb thymidine synthesis are largely inactive against P. aeruginosa.Here we characterize fluorofolin, a dihydrofolate reductase (DHFR) inhibitor derived from Irresistin-16, that exhibits significant activity against P. aeruginosa in culture and in a mouse thigh Infection model. Fluorofolin is active against a wide range of clinical P. aeruginosa isolates resistant to known Antibiotics. Metabolomics and in vitro assays using purified folA confirm that fluorofolin inhibits P. aeruginosa DHFR. Importantly, in the presence of thymine supplementation, fluorofolin activity is selective for P. aeruginosa. Resistance to fluorofolin can emerge through overexpression of the efflux pumps MexCD-OprJ and MexEF-OprN, but these mutants also decrease pathogenesis. Our findings demonstrate how understanding species-specific genetic differences can enable selective targeting of important pathogens while revealing trade-offs between resistance and pathogenesis.

Figures
Products