PMID:20660686

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Citation

Singh, R, Ledesma, KR, Chang, KT and Tam, VH (2010) Impact of recA on levofloxacin exposure-related resistance development.Antimicrob. Agents Chemother. 54:4262-8

Abstract

Genetic mutations are one of the major mechanisms by which bacteria acquire drug resistance. One of the known mechanisms for inducing mutations is the SOS response system. We investigated the effect of disrupting recA, an inducer of the SOS response, on resistance development using an in vitro hollow-fiber infection model. A clinical Staphylococcus aureus isolate and a laboratory wild-type strain of Escherichia coli were compared to their respective recA-deleted isogenic daughter isolates. Approximately 2 × 10(5) CFU/ml of bacteria were subjected to escalating levofloxacin exposures for up to 120 h. Serial samples were obtained to ascertain simulated drug exposures and total and resistant bacterial burdens. Quinolone resistance determining regions of gyrA and grlA (parC for E. coli) in levofloxacin-resistant isolates were sequenced to confirm the mechanism of resistance. The preexposure MICs of the recA-deleted isolates were 4-fold lower than those of their respective parents. In S. aureus, a lower area under the concentration-time curve over 24 h at steady state divided by the MIC (AUC/MIC) was required to suppress resistance development in the recA-deleted mutant (an AUC/MIC of >23 versus an AUC/MIC of >32 was necessary in the mutant versus the parent isolate, respectively), and a prominent difference in the total bacterial burden was observed at 72 h. Using an AUC/MIC of approximately 30, E. coli resistance emergence was delayed by 24 h in the recA-deleted mutant. Diverse mutations in gyrA were found in levofloxacin-resistant isolates recovered. Disruption of recA provided additional benefits apart from MIC reduction, attesting to its potential role for pharmacologic intervention. The clinical relevance of our findings warrants further investigations.

Links

PubMed Online version:10.1128/AAC.00168-10

Keywords

Anti-Bacterial Agents; Bacterial Proteins; Chromatography, High Pressure Liquid; Escherichia coli; Microbial Sensitivity Tests; Mutation; Ofloxacin; Rec A Recombinases; Staphylococcus aureus

Main Points of the Paper

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Materials and Methods Used

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Phenotype Annotations

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Phenotype of Taxon Information Genotype Information (if known) Condition Information OMP ID OMP Term Name ECO ID ECO Term Name Notes Status

a mutation or genetic difference within a strain

  • Taxon: Escherichia coli
  • Strain: K-12
  • Substrain: MG1655 relA(del)
  • NCBI Taxon ID: 83333
  • Genotype of Reference Strain: recA+
  • Genotype of Experimental Strain : recA(del)
  • Reference Condition:
OMP:0006040

decreased resistance to quinolone

ECO:0000016

loss-of-function mutant phenotype evidence

The recA(del) mutation reduced the MIC of levofloxacin (CHEBI:63598) to 25% that of the recA+ parent (described in text).

a mutation or genetic difference within a strain

  • Taxon: Escherichia coli
  • Strain: K-12
  • Substrain: MG1655
  • NCBI Taxon ID: 83333
  • Genotype of Reference Strain: recA+
  • Genotype of Experimental Strain : recA(del)
  • Reference Condition:
ECO:0000016

loss-of-function mutant phenotype evidence

The recA(del) mutation delays the regrowth and emergence of resistant mutants by 24 h in a hollow-fiber infection model (Fig. 4).


Notes

A recA(del) mutation had a much more profound effect on appearance of resistance mutants in S. aureus (Fig. 2 and Fig. 3).

References

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