Gallium-mediated siderophore quenching as an evolutionarily robust antibacterial treatment.
OBJECTIVE
Conventional antibiotics select strongly for resistance and are consequently losing efficacy worldwide. Extracellular quenching of shared virulence factors could represent a more promising strategy because (i) it reduces the available routes to resistance (as extracellular action precludes any mutations blocking a drug's entry into cells or hastening its exit) and (ii) it weakens selection for resistance, as fitness benefits to emergent mutants are diluted across all cells in a cooperative collective. Here, we tested this hypothesis empirically.


METHODS
We used gallium to quench the iron-scavenging siderophores secreted and shared among pathogenic Pseudomonas aeruginosa bacteria, and quantitatively monitored its effects on growth in vitro. We assayed virulence in acute infections of caterpillar hosts (Galleria mellonella), and tracked resistance emergence over time using experimental evolution.


RESULTS
Gallium strongly inhibited bacterial growth in vitro, primarily via its siderophore quenching activity. Moreover, bacterial siderophore production peaked at intermediate gallium concentrations, indicating additional metabolic costs in this range. In vivo, gallium attenuated virulence and growth-even more so than in infections with siderophore-deficient strains. Crucially, while resistance soon evolved against conventional antibiotic treatments, gallium treatments retained their efficacy over time.


CONCLUSIONS
Extracellular quenching of bacterial public goods could offer an effective and evolutionarily robust control strategy.
Institute of Plant Biology, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland; Swiss Federal Institute of Aquatic Science and Technology (Eawag), Environmental Microbiology, Überlandstrasse 133, 8600 Dübendorf, Switzerland; Institute of Evolutionary Biology and Centre for Immunity, Infection and Evolution, University of Edinburgh, West Mains Road, Ashworth Laboratories, Edinburgh EH9 3JT, UK.
Adin
A
Ross-Gillespie
Michael
M
Weigert
Sam P
SP
Brown
Rolf
R
Kümmerli
Pseudomonas; antivirulence therapy; experimental evolution; public good quenching; resistance