Perturbation of iron homeostasis promotes the evolution of antibiotic resistance

Orsolya Méhi, Balázs Bogos, Bálint Csörgo, Ferenc Pál, Ákos Nyerges, B. Papp, C. Pál

Research output: Article

19 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2793-2804
Number of pages12
JournalMolecular Biology and Evolution
Volume31
Issue number10
DOIs
Publication statusPublished - okt. 1 2014

Fingerprint

antibiotic resistance
homeostasis
Microbial Drug Resistance
Homeostasis
Iron
perturbation
iron
fur
mutagenesis
Mutagenesis
antibiotics
SOS response (genetics)
Anti-Bacterial Agents
ciprofloxacin
Gene Expression Profiling
storage proteins
Ciprofloxacin
Chelating Agents
chelating agents
transcriptomics

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Medicine(all)

Cite this

Perturbation of iron homeostasis promotes the evolution of antibiotic resistance. / Méhi, Orsolya; Bogos, Balázs; Csörgo, Bálint; Pál, Ferenc; Nyerges, Ákos; Papp, B.; Pál, C.

In: Molecular Biology and Evolution, Vol. 31, No. 10, 01.10.2014, p. 2793-2804.

Research output: Article

Méhi, Orsolya ; Bogos, Balázs ; Csörgo, Bálint ; Pál, Ferenc ; Nyerges, Ákos ; Papp, B. ; Pál, C. / Perturbation of iron homeostasis promotes the evolution of antibiotic resistance. In: Molecular Biology and Evolution. 2014 ; Vol. 31, No. 10. pp. 2793-2804.
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