Gallium-mediated siderophore quenching as an evolutionarily robust antibacterial treatment

Background and objectives: 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 (a) it reduces the available routes to resistance (since extracellular action precludes any mutations blocking a drug's entry into cells or hastening its exit) and (b) it weakens selection for resistance, since fitness benefits to emergent mutants are diluted across all cells in a cooperative collective. Here, we tested this hypothesis empirically. Methodology: 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 ...