Chemical and Biomolecular Insights into the Staphylococcus aureus Agr Quorum Sensing System: Current Progress and Ongoing Challenges

Abstract

Staphylococcus aureus is a ubiquitous bacterium that has become a major threat to human health due to its extensive toxin production and tremendous capacity for antibiotic resistance (e. g., MRSA “superbug” infections). Amid a worsening antibiotic resistance crisis, new strategies to combat this deadly microbe that remove the selective pressure of traditional approaches are in high demand. S. aureus utilizes an accessory gene regulator (agr) quorum sensing network to monitor its local cellular population and trigger a devastating communal attack, like an invading horde, once a threshold cell density has been reached. The role of the agr system in a range of disease types is still being unraveled. Herein, we discuss the present‐day biochemical understanding of agr along with unresolved details, describe its connection to the progression of infection, and review how chemical strategies have been implemented to study and intercept this signaling pathway. This research is illuminating the potential of agr as an anti‐virulence target in S. aureus and should inform the study of similar, yet less studied, agr systems in related bacterial pathogens.

Abiotic Small Molecule Inhibitors and Activators of the LasR Quorum Sensing Receptor in Pseudomonas aeruginosa with Potencies Comparable or Surpassing N-Acyl Homoserine Lactones

“…Further synthetic studies on this scaffold can clarify whether this improvement in potency is a function of the different ring identity (phenyl vs benzothiazole), substituents on the rings, the functional groups that link them (i.e., ester vs sulfonamide), or a combination thereof. The class III compound set (Figure 3), composed of an alphabenzisoxazole-acetamide linked at the 3′ position of the benzisoxazole to a phenol derivative by way of an internal alkyne, contained the second of the two most potent LasR antagonists (7) and the most efficacious LasR antagonist in this study (8, Table 1). Compound 7, like 3, has a potency (IC 50 = 0.4 μM) that is comparable to V-40, yet is 2-fold more efficacious than 3.…”

“…Many common bacteria communicate using low molecular weight molecules, or “autoinducers,” in a phenomenon known as quorum sensing (QS) . This cell-to-cell signaling process allows populations of bacteria to gauge their local densities and at high cell numbers engage in group-beneficial behaviors, some of which are relevant to human health, agriculture, and industrial processes. , The chemical nature of QS, dependent on the concentration of a signal in the local bacterial environment, has attracted many researchers to develop chemical strategies to divert or alter the sensing of these signals. , Our research group and others have been actively involved in the development of non-native small molecules and peptides capable of competing with native QS signal pathways. ,− Such compounds have utility as tools to delineate the roles of this complex signaling mechanism in infection and host-microbe interactions. , …”