Scientific article
Open access

Involvement of Fe uptake systems and AmpC β-lactamase in susceptibility to the siderophore monosulfactam BAL30072 in Pseudomonas aeruginosa

Published inAntimicrobial agents and chemotherapy, vol. 57, no. 5, p. 2095-2102
Publication date2013

BAL30072 is a monosulfactam conjugated with an iron-chelating dihydroxypyridone moiety. It is active against Gram-negative bacteria, including multidrug-resistant Pseudomonas aeruginosa. We selected mutants with decreased susceptibilities to BAL30072 in P. aeruginosa PAO1 under a variety of conditions. Under iron-deficient conditions, mutants with overexpression of AmpC β-lactamase predominated. These mutants were cross-resistant to aztreonam and ceftazidime. Similar mutants were obtained after selection at >16× the MIC in iron-sufficient conditions. At 4× to 8× the MIC, mutants with elevated MIC for BAL30072 but unchanged MICs for aztreonam or ciprofloxacin were selected. The expression of ampC and the major efflux pump genes were also unchanged. These BAL30072-specific mutants were characterized by transcriptome analysis, which revealed upregulation of the Fe-dicitrate operon, FecIRA. Whole-genome sequencing showed that this resulted from a single nucleotide change in the Fur-box of the fecI promoter. Overexpression of either the FecI ECF sigma factor or the FecA receptor increased BAL30072 MICs 8- to 16-fold. A fecI mutant and a fecA mutant of PAO1 were hypersusceptible to BAL30072 (MICs < 0.06 μg/ml). The most downregulated gene belonged to the pyochelin synthesis operon, although mutants in pyochelin receptor or synthesis genes had unchanged MICs. The piuC gene, coding for a Fe(II)-dependent dioxygenase located next to the piuA iron receptor gene, was also downregulated. The MICs of BAL30072 for piuC and piuA transposon mutants were increased 8- and 16-fold, respectively. We conclude that the upregulation of the Fe-dicitrate system impacts the expression of other TonB-dependent iron transporters and that PiuA and PiuC contribute to the susceptibility of P. aeruginosa PAO1 to BAL30072.

  • Anti-Bacterial Agents/pharmacology
  • Aztreonam/pharmacology
  • Bacterial Proteins/genetics/metabolism
  • Carrier Proteins/genetics/metabolism
  • Ceftazidime/pharmacology
  • Drug Resistance, Multiple, Bacterial/drug effects/genetics
  • Gene Expression Regulation, Bacterial/drug effects
  • Ion Transport/drug effects
  • Iron/deficiency/metabolism
  • Microbial Sensitivity Tests
  • Monobactams/pharmacology
  • Mutation
  • Operon
  • Phenols/metabolism
  • Pseudomonas aeruginosa/drug effects/genetics/metabolism
  • Siderophores/pharmacology
  • Sigma Factor/genetics/metabolism
  • Thiazoles/metabolism/pharmacology
  • Beta-Lactamases/genetics/metabolism
Citation (ISO format)
VAN DELDEN, Christian, PAGE, Malcolm G P, KOHLER, Thilo. Involvement of Fe uptake systems and AmpC β-lactamase in susceptibility to the siderophore monosulfactam BAL30072 in Pseudomonas aeruginosa. In: Antimicrobial agents and chemotherapy, 2013, vol. 57, n° 5, p. 2095–2102. doi: 10.1128/AAC.02474-12
Main files (1)
Article (Published version)
ISSN of the journal0066-4804

Technical informations

Creation12/17/2014 1:14:00 PM
First validation12/17/2014 1:14:00 PM
Update time03/14/2023 10:28:57 PM
Status update03/14/2023 10:28:57 PM
Last indexation08/29/2023 1:42:35 PM
All rights reserved by Archive ouverte UNIGE and the University of GenevaunigeBlack