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

Quorum sensing antagonism from marine organisms

With the global emergence of multiresistant bacteria there is an increasing demand for development of new treatments to combat pathogens. Bacterial cell–cell communication [quorum sensing (QS)] regulates expression of virulence factors in a number of bacterial pathogens and is a new promising target for the control of infectious bacteria. We present the results of screening of 284 extracts of marine organisms from the Great Barrier Reef, Australia, for their inhibition of QS. Of the 284 extracts, 64 (23%) were active in a general, LuxR-derived QS screen, and of these 36 (56%) were also active in a specific Pseudomonas aeruginosa QS screen. Extracts of the marine sponge Luffariella variabilis proved active in both systems. The secondary metabolites manoalide, manoalide monoacetate, and secomanoalide isolated from the sponge showed strong QS inhibition of a lasB::gfp(ASV) fusion, demonstrating the potential for further identification of specific QS antagonists from marine organisms