Staphylococcus aureus is one of the most frequent worldwide causes of morbidity and mortality due to an infectious agent. This pathogen can cause a wide variety of diseases, ranging from moderately severe skin infections to fatal pneumonia and sepsis. Treatment of S. aureus infections is complicated by antibiotic resistance and a working vaccine is not available. There has been ongoing and increasing interest in the extraordinarily high number of toxins and other virulence determinants that S. aureus produces and how they impact disease. In this review, we will give an overview of how S. aureus initiates and maintains infection and discuss the main determinants involved. A more in-depth understanding of the function and contribution of S. aureus virulence determinants to S. aureus infection will enable us to develop anti-virulence strategies to counteract the lack of an anti-S. aureus vaccine and the ever-increasing shortage of working antibiotics against this important pathogen.

Social interactions play an increasingly recognized key role in bacterial physiology 1 . One of the best studied is quorum sensing (QS), a mechanism by which bacteria sense and respond to the status of cell density 2 . While QS is generally deemed crucial for bacterial survival, QS-dysfunctional mutants frequently arise in in-vitro culture. This has been explained by the fitness cost an individual mutant, a “quorum cheater”, saves at the expense of the community 3 . QS mutants are also often isolated from biofilm-associated infections, including cystic fibrosis lung infection 4 , as well as medical device infection and associated bacteremia 5 – 7 . However, despite the frequently proposed use of QS blockers to control virulence 8 , the mechanisms underlying QS dysfunctionality during infection have remained poorly understood. Here we show that in the major human pathogen Staphylococcus aureus , QS-dysfunctional mutants arise exclusively in biofilm infection, while in non-biofilm-associated infection there is a high selective pressure to maintain QS control. We demonstrate that this infection-type dependence is due to QS-dysfunctional bacteria having a significant survival advantage in biofilm infection, because they form dense and enlarged biofilms that provide resistance to phagocyte attacks. Our results link the benefit of QS-dysfunctional mutants in vivo to biofilm-mediated immune evasion, thus to mechanisms that are specific to the in-vivo setting. Notably, our findings explain why QS mutants are frequently isolated from biofilm-associated infections and provide guidance for the therapeutic application of QS blockers.

Summary The production and regulation of defensive specialized metabolites play a central role in pathogen resistance in maize (Zea mays) and other plants. Therefore, identification of genes involved in plant specialized metabolism can contribute to improved disease resistance. We used comparative metabolomics to identify previously unknown antifungal metabolites in maize seedling roots, and investigated the genetic and physiological mechanisms underlying their natural variation using quantitative trait locus mapping and comparative transcriptomics approaches. Two maize metabolites, smilaside A (3,6‐diferuloyl‐3′,6′‐diacetylsucrose) and smiglaside C (3,6‐diferuloyl‐2′,3′,6′‐triacetylsucrose), were identified that could contribute to maize resistance against Fusarium graminearum and other fungal pathogens. Elevated expression of an ethylene signaling gene, ETHYLENE INSENSITIVE 2 (ZmEIN2), co‐segregated with a decreased smilaside A : smiglaside C ratio. Pharmacological and genetic manipulation of ethylene availability and sensitivity in vivo indicated that, whereas ethylene was required for the production of both metabolites, the smilaside A : smiglaside C ratio was negatively regulated by ethylene sensitivity. This ratio, rather than the absolute abundance of these two metabolites, was important for maize seedling root defense against F. graminearum. Ethylene signaling regulates the relative abundance of the two F. graminearum‐resistance‐related metabolites and affects resistance against F. graminearum in maize seedling roots.