Dataset Information

Selection for increased quorum-sensing cooperation in Pseudomonas aeruginosa through the shut-down of a drug resistance pump.

ABSTRACT: The opportunistic pathogen Pseudomonas aeruginosa employs a hierarchical quorum-sensing network to regulate virulence factor production that cooperatively benefit the population at a cost to the individual. It has been argued that the evolution of a cooperative mutant in a quorum sensing-suppressed population would be hampered through its exploitation by neighboring non-mutant cells. It remains unclear whether mechanisms which overcome this exploitation exist. Here we investigate the regain of quorum-sensing cooperation by evolving a mutant of the lasR master quorum-sensing regulator. The mutant regained partial cooperative growth through null mutations in mexT, which codes for an activator of the MexEF-OprN multidrug-resistant pump. We find that these mutations enhance cooperative growth in both the lasR mutant and wild-type backgrounds through the activation of the RhlIR system. We show that the regain of cooperation in mexT mutants is mediated by the reduction in MexEF-OprN activity, whereas an additional source of private benefit is mostly mexEF-oprN-independent. Finally, we show that addition of antibiotics for which resistance is mediated by MexEF-OprN prevents the selection of increased cooperation at sub-MIC concentrations. MexT, therefore, not only links private and public goods, but also exposes conflicts between selection for antibiotic resistance and enhanced cooperation.

SUBMITTER: Oshri RD

PROVIDER: S-EPMC6154968 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Selection for increased quorum-sensing cooperation in Pseudomonas aeruginosa through the shut-down of a drug resistance pump.

Oshri Ron D RD Zrihen Keren S KS Shner Itzhak I Omer Bendori Shira S Eldar Avigdor A

The ISME journal 20180620 10

The opportunistic pathogen Pseudomonas aeruginosa employs a hierarchical quorum-sensing network to regulate virulence factor production that cooperatively benefit the population at a cost to the individual. It has been argued that the evolution of a cooperative mutant in a quorum sensing-suppressed population would be hampered through its exploitation by neighboring non-mutant cells. It remains unclear whether mechanisms which overcome this exploitation exist. Here we investigate the regain of q ...[more]

PMID: 29925881

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Project description: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.

Dataset Information

Selection for increased quorum-sensing cooperation in Pseudomonas aeruginosa through the shut-down of a drug resistance pump.

Publications

Selection for increased quorum-sensing cooperation in Pseudomonas aeruginosa through the shut-down of a drug resistance pump.

Similar Datasets

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