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Pyoverdine-antibiotic combination treatment: its efficacy and effects on resistance evolution in Escherichia coli
Vera Vollenweider1, Flavie Roncoroni1, Rolf Kümmerli1
1Department of Quantitative Biomedicine, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland.
Abstract:
Antibiotic resistance is a growing concern for global health, demanding innovative and effective strategies to combat pathogenic bacteria. Pyoverdines, iron-chelating siderophores produced by environmental Pseudomonas spp., present a novel class of promising compounds to induce growth arrest in pathogens through iron starvation. While we 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 investigated the propensity of three Escherichia coli strains to evolve resistance against pyoverdine, the cephalosporin antibiotic ceftazidime, and their combination. We used a naive E. coli wildtype strain and two isogenic variants carrying the bla TEM-1 β-lactamase gene on either the chromosome or a costly multicopy plasmid to explore the influence of genetic background on selection for resistance. We found that strong resistance against ceftazidime and weak resistance against pyoverdine evolved in all E. coli variants under single treatment. Ceftazidime resistance was linked to mutations in outer membrane porin genes (envZ and ompF), whereas pyoverdine resistance was associated with mutations in the oligopeptide permease (opp) operon. In contrast, ceftazidime resistance phenotypes were attenuated under combination treatment, especially for the E. coli variant carrying bla TEM-1 on the multicopy plasmid. Altogether, our results show that ceftazidime and pyoverdine interact neutrally and that pyoverdine as an antibacterial is particularly potent against plasmid-carrying E. coli strains, presumably because iron starvation compromises both cellular metabolism and plasmid replication.
Insights
Pyoverdine, an iron-chelating compound, shows potential against antibiotic-resistant bacteria. Combining pyoverdine with ceftazidime (an antibiotic) attenuated resistance, especially in plasmid-carrying E. coli strains.
Area of Science:
- Microbiology
- Infectious Diseases
- Drug Discovery
Background:
- Antibiotic resistance poses a significant global health threat.
- Pyoverdines, siderophores from *Pseudomonas* spp., induce bacterial growth arrest via iron starvation.
- The interaction of pyoverdines with antibiotics and their impact on resistance evolution are largely unexplored.
Purpose of the Study:
- To investigate the evolution of resistance in *Escherichia coli* to pyoverdine, ceftazidime, and their combination.
- To determine the influence of genetic background, including the presence of the *bla*TEM-1 β-lactamase gene on plasmids, on resistance selection.
- To understand the interaction between pyoverdine and ceftazidime in the context of antibiotic resistance.
Main Methods:
- Experimental evolution of three *E. coli* strains (wildtype and two isogenic variants with *bla*TEM-1 on chromosome or plasmid) under single and combination treatments.
- Genomic analysis to identify mutations conferring resistance.
- Phenotypic characterization of resistance levels to pyoverdine and ceftazidime.
Main Results:
- Single treatment with ceftazidime or pyoverdine led to evolved resistance in all *E. coli* strains.
- Ceftazidime resistance was associated with mutations in porin genes (*envZ*, *ompF*), while pyoverdine resistance involved the oligopeptide permease (*opp*) operon.
- Combination treatment attenuated ceftazidime resistance, particularly in the plasmid-carrying strain, suggesting pyoverdine's enhanced efficacy against these variants.
Conclusions:
- Pyoverdine and ceftazidime exhibit neutral interactions.
- Pyoverdine demonstrates potent antibacterial activity against plasmid-carrying *E. coli*, likely due to compromised cellular metabolism and plasmid replication under iron starvation.
- Pyoverdine represents a promising strategy to combat antibiotic resistance, especially in strains with resistance plasmids.
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