Oxidative stress drives the selection of quorum sensing mutants in the <i>Staphylococcus aureus</i> population.

Abstract

Quorum sensing (QS) is the central mechanism by which social interactions within the bacterial community control bacterial behavior. QS-negative cells benefit by exploiting public goods produced by the QS-proficient population. Mechanisms to keep the balance between producers and nonproducers within the population are expected but have not been elucidated for peptide-based QS systems in gram-positive pathogens. The Agr system of <i>Staphylococcus aureus</i> comprises the secretion and sensing of an autoinducing peptide to activate its own expression via the response regulator AgrA as well as the expression of a regulatory RNAIII and <i>psm</i>α<i>/psm</i>ß coding for phenol-soluble modulins (PSMs). <i>Agr</i> mutants can be monitored on blood agar due to their nonhemolytic phenotype. In vitro evolution and competition experiments show that they readily accumulate in a process that is accelerated by ciprofloxacin, while the wild type (WT) is retained in the population at low numbers. However, <i>agr</i> mutants possess a fitness advantage only under aerobic conditions. Under hypoxia, Agr activity is increased but without the expected fitness cost. The Agr-imposed oxygen-dependent fitness cost is not due to a metabolic burden but due to the reactive oxygen species (ROS)-inducing capacity of the PSMs and RNAIII-regulated factors. Thus, selection of mutants is dictated by the QS system itself. Under aerobic conditions, emergence of <i>agr</i>-negative mutants may provide the population with a fitness advantage while hypoxia favors QS maintenance and even affords increased toxin production. The oxygen-driven tuning of the Agr system might be of importance to provide the pathogen with capabilities crucial for disease progression.