Critical Assessment of the Prospects of Quorum-Quenching Therapy for Staphylococcus aureus Infection

Staphylococcus aureus is an important pathogen that causes a high number of infections and is one of the leading causes of death in hospitalized patients. Widespread antibiotic resistance such as in methicillin-resistant S. aureus (MRSA) has prompted research into potential anti-virulence-targeted approaches. Targeting the S. aureus accessory gene regulator (Agr) quorum-sensing system, a master regulator of virulence, is the most frequently proposed anti-virulence strategy for S. aureus. While much effort has been put into the discovery and screening for Agr inhibitory compounds, in vivo analysis of their efficacy in animal infection models is still rare and reveals various shortcomings and problems. These include (i) an almost exclusive focus on topical skin infection models, (ii) technical problems that leave doubt as to whether observed in vivo effects are due to quorum-quenching, and (iii) the discovery of counterproductive biofilm-increasing effects. Furthermore, potentially because of the latter, invasive S. aureus infection is associated with Agr dysfunctionality. Altogether, the potential of Agr inhibitory drugs is nowadays seen with low enthusiasm given the failure to provide sufficient in vivo evidence for their potential after more than two decades since the initiation of such efforts. However, current Agr inhibition-based probiotic approaches may lead to a new application of Agr inhibition strategies in preventing S. aureus infections by targeting colonization or for otherwise difficult-to-treat skin infections such as atopic dermatitis.

Automated summary

Staphylococcus aureus is a significant pathogen responsible for numerous infections and causing high mortality rates in hospitalized patients. The emergence of antibiotic resistance, particularly methicillin-resistant S. aureus (MRSA), has prompted the exploration of alternative anti-virulence strategies. Targeting the S. aureus accessory gene regulator (Agr) quorum-sensing system, a key regulator of virulence, has been proposed as the most common anti-virulence approach. However, there is limited in vivo evidence for the efficacy of Agr inhibition, and potential concerns regarding biofilm formation and functional implications on invasive S. aureus infections.