Probing the evolutionary robustness of two repurposed drugs targeting iron uptake inPseudomonas aeruginosa
Preprint
- 2 October 2017
- preprint
- other
- Published by Cold Spring Harbor Laboratory
- p. 195974
- https://doi.org/10.1101/195974
Abstract
Background and objectives: 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 probe the evolutionary robustness of two repurposed drugs, gallium and flucytosine, targeting the iron-scavenging pyoverdine of the opportunistic human pathogenPseudomonas aeruginosa.Methodology: We subjected replicated cultures of bacteria to two concentrations of each drug for 20 consecutive days in human serum as an ex-vivo infection model. We screened evolved populations and clones for resistance phenotypes, including the restoration of growth and pyoverdine production, and the evolution of iron uptake by-passing mechanisms. We whole-genome sequenced evolved clones to identify the genetic basis of resistance.Results: We found that mutants resistant against anti-virulence treatments readily arose, but their selective spreading varied between treatments. Flucytosine resistance quickly spread in all populations due to disruptive mutations inupp, a gene encoding an enzyme required for flucytosine activation. Conversely, resistance against gallium arose only sporadically, and was based on mutations in transcriptional regulators, upregulating pyocyanin production, a redox-active molecule promoting siderophore-independent iron acquisition. The spread of gallium resistance could be hampered because pyocyanin-mediated iron delivery benefits resistant and susceptible cells alike.Conclusions and implications: Our work highlights that anti-virulence treatments are not evolutionarily robustper se. Instead, evolutionary robustness is a relative measure, with specific treatments occupying different positions on a continuous scale.Keywords
Other Versions
- Published version: Version Evolution, Medicine, and Public Health, 2018, preprints
This publication has 74 references indexed in Scilit:
- Repurposing the antimycotic drug flucytosine for suppression of Pseudomonas aeruginosa pathogenicityProceedings of the National Academy of Sciences of the United States of America, 2013
- Bacterial cheating drives the population dynamics of cooperative antibiotic resistance plasmidsMolecular Systems Biology, 2013
- A dynamic and intricate regulatory network determines Pseudomonas aeruginosa virulenceNucleic Acids Research, 2012
- Bacterial Quorum Sensing and Metabolic Incentives to CooperateScience, 2012
- Drugs that target pathogen public goods are robust against evolved drug resistanceEvolutionary Applications, 2012
- Quorum quenching quandary: resistance to antivirulence compoundsThe ISME Journal, 2011
- The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing dataGenome Research, 2010
- Fast and accurate short read alignment with Burrows–Wheeler transformBioinformatics, 2009
- Phenotypic plasticity of a cooperative behaviour in bacteriaJournal of Evolutionary Biology, 2009
- The potential of desferrioxamine-gallium as an anti- Pseudomonas therapeutic agentProceedings of the National Academy of Sciences of the United States of America, 2008