Siderophores promote cooperative interspecies and intraspecies cross-protection against antibiotics in vitro

Anna Clara M. Galdino, Mylene Vaillancourt, Diana Celedonio, Kara Huse, Yohei Doi, Janet S. Lee, Peter Jorth

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)


The antibiotic cefiderocol hijacks iron transporters to facilitate its uptake and resists β-lactamase degradation. While effective, resistance has been detected clinically with unknown mechanisms. Here, using experimental evolution, we identified cefiderocol resistance mutations in Pseudomonas aeruginosa. Resistance was multifactorial in host-mimicking growth media, led to multidrug resistance and paid fitness costs in cefiderocol-free environments. However, kin selection drove some resistant populations to cross-protect susceptible individuals from killing by increasing pyoverdine secretion via a two-component sensor mutation. While pyochelin sensitized P. aeruginosa to cefiderocol killing, pyoverdine and the enterobacteria siderophore enterobactin displaced iron from cefiderocol, preventing uptake by susceptible cells. Among 113 P. aeruginosa intensive care unit clinical isolates, pyoverdine production directly correlated with cefiderocol tolerance, and high pyoverdine producing isolates cross-protected susceptible P. aeruginosa and other Gram-negative bacteria. These in vitro data show that antibiotic cross-protection can occur via degradation-independent mechanisms and siderophores can serve unexpected protective cooperative roles in polymicrobial communities.

Original languageEnglish
Pages (from-to)631-646
Number of pages16
JournalNature Microbiology
Issue number3
Publication statusPublished - 03-2024
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Immunology
  • Applied Microbiology and Biotechnology
  • Genetics
  • Microbiology (medical)
  • Cell Biology


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