Probing the evolutionary robustness of two repurposed drugs targeting iron uptake in Pseudomonas aeruginosa
Treatments that inhibit the expression or functioning of bacterial virulence factors hold great promise to be both effective and exert weaker selection for resistance than conventional antibiotics. However, the evolutionary robustness argument, based on the idea that anti-virulence treatments disarm rather than kill pathogens, is controversial. Here we compared the evolutionary robustness of two repurposed drugs, gallium and flucytosine, targeting the iron-scavenging pyoverdine of the opportunistic human pathogen Pseudomonas aeruginosa. After exposing bacteria to treatments for 20 days in human blood serum, as an ex-vivo infection model, we found that resistance against flucytosine quickly arose and spread in all populations. Genetic analysis revealed that mutations in upp, a gene encoding an enzyme required for flucytosine activation, are responsible for resistance evolution. Conversely, resistance against gallium arose only sporadically. Resistance mechanisms were based on mutations in transcriptional regulators, which resulted in the upregulation of pyocyanin, a redox-active molecule promoting siderophore-independent iron acquisition. Our work highlights that mutants resistant against anti-virulence treatments can easily arise, but their selective spreading varies considerably between treatments. This indicates that anti-virulence treatments are not evolutionarily robust per se. Instead, evolutionary robustness is a relative measure, with specific treatments occupying different positions on a continuous scale.
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