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

Autor: Thilo Köhler, Christian van Delden, Malcolm G. P. Page
Rok vydání: 2013
Předmět:
Siderophore
Operon
Mutant
Siderophores
Aztreonam
medicine.disease_cause
Ceftazidime
Ion Transport/drug effects
chemistry.chemical_compound
Drug Resistance
Multiple
Bacterial/drug effects/genetics
Sigma factor
Drug Resistance
Multiple
Bacterial
Pharmacology (medical)
ddc:616
Siderophores/pharmacology
Iron Deficiencies
Pseudomonas aeruginosa/drug effects/genetics/metabolism
Anti-Bacterial Agents
Infectious Diseases
Carrier Proteins/genetics/metabolism
Pseudomonas aeruginosa
Bacterial Proteins/genetics/metabolism
Efflux
Ceftazidime/pharmacology
Iron/deficiency/metabolism
Monobactams
Iron
Sigma Factor
Microbial Sensitivity Tests
Biology
Aztreonam/pharmacology
beta-Lactamases
Microbiology
Anti-Bacterial Agents/pharmacology
Thiazoles/metabolism/pharmacology
Bacterial Proteins
Phenols
Mechanisms of Resistance
medicine
Phenols/metabolism
Gene
Gene Expression Regulation
Bacterial/drug effects
Sigma Factor/genetics/metabolism
Pharmacology
Ion Transport
Gene Expression Regulation
Bacterial
Beta-Lactamases/genetics/metabolism
Thiazoles
chemistry
Monobactams/pharmacology
Mutation
bacteria
Carrier Proteins
Zdroj: Antimicrobial Agents and Chemotherapy, Vol. 57, No 5 (2013) pp. 2095-102
ISSN: 1098-6596
0066-4804
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: