title: Perturbation of iron homeostasis promotes the evolution of antibiotic resistance.
abstract: Evolution of antibiotic resistance in microbes is frequently achieved by acquisition of spontaneous mutations during antimicrobial therapy. Here, we demonstrate that inactivation of a central transcriptional regulator of iron homeostasis (Fur) facilitates laboratory evolution of ciprofloxacin resistance in Escherichia coli. To decipher the underlying molecular mechanisms, we first performed a global transcriptome analysis and demonstrated that the set of genes regulated by Fur changes substantially in response to antibiotic treatment. We hypothesized that the impact of Fur on evolvability under antibiotic pressure is due to the elevated intracellular concentration of free iron and the consequent enhancement of oxidative damage-induced mutagenesis. In agreement with expectations, overexpression of iron storage proteins, inhibition of iron transport, or anaerobic conditions drastically suppressed the evolution of resistance, whereas inhibition of the SOS response-mediated mutagenesis had only a minor effect. Finally, we provide evidence that a cell permeable iron chelator inhibits the evolution of resistance. In sum, our work revealed the central role of iron metabolism in the de novo evolution of antibiotic resistance, a pattern that could influence the development of novel antimicrobial strategies.
authors: Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary.
authors: Orsolya
authors: O
authors: Méhi
authors: Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary.
authors: Balázs
authors: B
authors: Bogos
authors: Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary.
authors: Bálint
authors: B
authors: Csörgő
authors: Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary.
authors: Ferenc
authors: F
authors: Pál
authors: Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary.
authors: Akos
authors: A
authors: Nyerges
authors: Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary.
authors: Balázs
authors: B
authors: Papp
authors: Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary pal.csaba@brc.mta.hu.
authors: Csaba
authors: C
authors: Pál
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics*; D002939:Ciprofloxacin / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D048168:Escherichia coli K12 / Q000187:drug effects / Q000235:genetics*; D019143:Evolution, Molecular; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D006706:Homeostasis; D007501:Iron / Q000378:metabolism*; D016296:Mutagenesis; D018384:Oxidative Stress; D012097:Repressor Proteins / Q000235:genetics*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D012097:Repressor Proteins; C068477:ferric uptake regulating proteins, bacterial; D002939:Ciprofloxacin; D007501:Iron
keywords: SOS response; antibiotic resistance; bacterial evolution