Journal Article

Quorum Sensing Inhibition Selects for Virulence and Cooperation in Pseudomonas aeruginosa

Buckling, Angus, Perron, Gabriel G., Köhler, Thilo, van Delden, Christian

2010

Overview

With the rising development of bacterial resistance the search for new medical treatments beyond conventional antimicrobials has become a key aim of public health research. Possible innovative strategies include the inhibition of bacterial virulence. However, consideration must be given to the evolutionary and environmental consequences of such new interventions. Virulence and cooperative social behaviour of the bacterium Pseudomonas aeruginosa rely on the quorum-sensing (QS) controlled production of extracellular products (public goods). Hence QS is an attractive target for anti-virulence interventions. During colonization, non-cooperating (and hence less virulent) P. aeruginosa QS-mutants, benefiting from public goods provided by wild type isolates, naturally increase in frequency providing a relative protection from invasive infection. We hypothesized that inhibition of QS-mediated gene expression removes this growth advantage and selection of less virulent QS-mutants, and maintains the predominance of more virulent QS-wild type bacteria. We addressed this possibility in a placebo-controlled trial investigating the anti-QS properties of azithromycin, a macrolide antibiotic devoid of bactericidal activity on P. aeruginosa, but interfering with QS, in intubated patients colonized by P. aeruginosa. In the absence of azithromycin, non-cooperating (and hence less virulent) lasR (QS)-mutants increased in frequency over time. Azithromycin significantly reduced QS-gene expression measured directly in tracheal aspirates. Concomitantly the advantage of lasR-mutants was lost and virulent wild-type isolates predominated during azithromycin treatment. We confirmed these results in vitro with fitness and invasion experiments. Azithromycin reduced growth rate of the wild-type, but not of the lasR-mutant. Furthermore, the lasR-mutant efficiently invaded wild-type populations in the absence, but not in the presence of azithromycin. These in vivo and in vitro results demonstrate that anti-virulence interventions based on QS-blockade diminish natural selection towards reduced virulence and therefore may increase the prevalence of more virulent genotypes in the Hospital environment. More generally, the impact of intervention on the evolution of virulence of pathogenic bacteria should be assessed.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Anti-Bacterial Agents - therapeutic use / Antibacterial agents / Azithromycin - therapeutic use / Bacteria / Bacteriology / Complications and side effects / Cooperation / Critical Illness / Deoxyribonucleic acid / DNA / Dosage and administration / Drug resistance in microorganisms / Drug Resistance, Bacterial - genetics / Drug therapy / Ecology/Evolutionary Ecology / Ecology/Population Ecology / Evolution, Molecular / Evolutionary Biology/Microbial Evolution and Genomics / Experiments / Genetic aspects / Hospitals / Humans / Infectious Diseases/Antimicrobials and Drug Resistance / Infectious Diseases/Bacterial Infections / Infectious Diseases/Nosocomial and Healthcare-Associated Infections / Infectious Diseases/Respiratory Infections / Intervention / Medical research / Microbiology / Microbiology/Microbial Evolution and Genomics / Mutation / Patients / Physiological aspects / Placebos / Pneumonia, Bacterial - drug therapy / Pneumonia, Bacterial - microbiology / Pseudomonas aeruginosa - drug effects / Pseudomonas aeruginosa - genetics / Pseudomonas aeruginosa - pathogenicity / Pseudomonas aeruginosa infections / Pseudomonas Infections - drug therapy / Pseudomonas Infections - microbiology / Public health / Quorum sensing / Quorum Sensing - drug effects / Quorum Sensing - genetics / Respiration, Artificial / Risk factors / Trachea - microbiology / Virulence