Pyoverdine-antibiotic combination treatment: its efficacy and effects on resistance evolution inEscherichia coli

Abstract

AbstractAntibiotic resistance is a growing concern for global health, demanding innovative and effective strategies to combat pathogenic bacteria. Pyoverdines, iron-chelating siderophores produced by environmentalPseudomonasspp., present a novel promising approach to induce growth arrest in pathogens through iron starvation. While we have previously demonstrated the efficacy of pyoverdines as antibacterials, our understanding of how these molecules interact with antibiotics and impact resistance evolution remains unknown. Here, we investigate the propensity of differentEscherichia colivariants to evolve resistance against pyoverdine, the cephalosporin antibiotic ceftazidime, and their combination. We found that strong resistance against ceftazidime and weak resistance against pyoverdine evolved in the wildtypeE. colistrain under single and combination treatment. Ceftazidime resistance was linked to mutations in outer membrane porin genes (envZandompF), whereas pyoverdine resistance was associated with mutations in the oligopeptide permease (opp) operon. In contrast, resistance phenotypes were attenuated under combination treatment, particularly in anE. colistrain carrying a costly multicopy plasmid. Altogether, our results show that pyoverdine as an antibacterial is particularly potent and evolutionarily robust against plasmid-carryingE. colistrains, presumably because iron starvation compromises both cellular metabolism and plasmid replication.