Effects of antibiotics on quorum sensing in Pseudomonas aeruginosa.
During infection, Pseudomonas aeruginosa employs bacterial communication (quorum sensing [QS]) to coordinate the expression of tissue-damaging factors. QS-controlled gene expression plays a pivotal role in the virulence of P. aeruginosa, and QS-deficient mutants cause less severe infections in animal infection models. Treatment of cystic fibrosis (CF) patients chronically infected with P. aeruginosa with the macrolide antibiotic azithromycin (AZM) has been demonstrated to improve the clinical outcome. Several studies indicate that AZM may accomplish its beneficial action in CF patients by impeding QS, thereby reducing the pathogenicity of P. aeruginosa. This led us to investigate whether QS inhibition is a common feature of antibiotics. We present the results of a screening of 12 antibiotics for their QS-inhibitory activities using a previously described QS inhibitor selector 1 strain. Three of the antibiotics tested, AZM, ceftazidime (CFT), and ciprofloxacin (CPR), were very active in the assay and were further examined for their effects on QS-regulated virulence factor production in P. aeruginosa. The effects of the three antibiotics administered at subinhibitory concentrations were investigated by use of DNA microarrays. Consistent results from the virulence factor assays, reverse transcription-PCR, and the DNA microarrays support the finding that AZM, CFT, and CPR decrease the expression of a range of QS-regulated virulence factors. The data suggest that the underlying mechanism may be mediated by changes in membrane permeability, thereby influencing the flux of N-3-oxo-dodecanoyl-L-homoserine lactone.
Skindersoe
Mette E
ME
Biomedical Microbiology, BioSys, Technical University of Denmark, Kgs. Lyngby DK-2800, Denmark.
Alhede
Morten
M
Phipps
Richard
R
Yang
Liang
L
Jensen
Peter O
PO
Rasmussen
Thomas B
TB
Bjarnsholt
Thomas
T
Tolker-Nielsen
Tim
T
Høiby
Niels
N
Givskov
Michael
M
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D017963:Azithromycin / Q000494:pharmacology; D001483:Base Sequence; D002442:Ceftazidime / Q000494:pharmacology; D002939:Ciprofloxacin / Q000494:pharmacology; D017931:DNA Primers / Q000235:genetics; D004269:DNA, Bacterial / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D005798:Genes, Bacterial / Q000187:drug effects; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D009894:Opportunistic Infections / Q000188:drug therapy / Q000382:microbiology; D016133:Polymerase Chain Reaction; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D053038:Quorum Sensing / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D014774:Virulence / Q000235:genetics
D000900:Anti-Bacterial Agents; D017931:DNA Primers; D004269:DNA, Bacterial; D002939:Ciprofloxacin; D017963:Azithromycin; D002442:Ceftazidime