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Mol Biol Evol. 2014 Oct;31(10):2793-804. doi: 10.1093/molbev/msu223. Epub 2014 Jul 24.

Perturbation of iron homeostasis promotes the evolution of antibiotic resistance.

Author information

1
Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary.
2
Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre of the Hungarian Academy of Sciences, Szeged, Hungary pal.csaba@brc.mta.hu.

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.

KEYWORDS:

SOS response; antibiotic resistance; bacterial evolution

PMID:
25063442
PMCID:
PMC4166929
DOI:
10.1093/molbev/msu223
[Indexed for MEDLINE]
Free PMC Article

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