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

Abstract

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.

Interkingdom Detection of Bacterial Quorum-Sensing Molecules by Mammalian Taste Receptors

“…It is involved in various bacterial functions in both Gram positive and negative bacteria, such as expression of virulence factors and evasion of immune response [ 19 ]. Quorum sensing relies on the production, release, and recognition of signaling molecules, often called auto-inducers [ 20 , 21 , 22 , 23 , 24 ]. When these extracellular quorum-sensing molecules reach a concentration threshold high enough to be recognized by bacterial receptor proteins, which directly reflects the bacterial density, the expression of specific genes is turned on or off.…”

“…When these extracellular quorum-sensing molecules reach a concentration threshold high enough to be recognized by bacterial receptor proteins, which directly reflects the bacterial density, the expression of specific genes is turned on or off. This prevents activation of certain pathogenic responses until the bacterial population is at a high enough density [ 20 , 21 , 22 , 23 , 24 ]. Genes regulated by quorum sensing often include virulence factors such as toxins or proteases that break down host tissue [ 20 , 21 , 22 , 23 , 24 ].…”

“…This prevents activation of certain pathogenic responses until the bacterial population is at a high enough density [ 20 , 21 , 22 , 23 , 24 ]. Genes regulated by quorum sensing often include virulence factors such as toxins or proteases that break down host tissue [ 20 , 21 , 22 , 23 , 24 ].…”

Pathogenic role of the staphylococcal accessory gene regulator quorum sensing system in atopic dermatitis

“…Our group has also reported that Agr-QS inhibitors suppress the virulence of S. aureus and reduce skin inflammation in a mouse model of inflammatory skin disease variants (Baldry et al, 2018;Nakagawa et al, 2020). There have been numerous attempts to target AgrA and AgrC and other targets for quorum quenching, but rare in vivo experiments have shown efficacy in animal infection models, and the fact that it was found to be counterproductive biofilm-increasing effects makes it uncertain whether it can actually be used for treatment (Otto, 2023). There are also emerging approaches to using bacteria competing against S. aureus for bacteriotherapy.…”

Quorum-sensing, intra- and inter-species competition in the staphylococci

“…Paradoxically, agr is required for skin colonization [19]. However, a functional agr system is dispensable for chronic, biofilm-related infections associated with, for example, implanted medical devices and cystic fibrosis [18]. Furthermore, allelic variation in agr genes contributes to intra-and inter-staphylococcal competition since the cognate agr signal molecule of one staphylococcal agr variant may inhibit agr in a strain possessing a different agr variant [20][21][22].…”