A structurally unrelated mimic of a Pseudomonas aeruginosa acyl-homoserine lactone quorum-sensing signal

Abstract

The pathogenic bacterium Pseudomonas aeruginosa uses acylhomoserine lactone quorum-sensing signals to coordinate the expression of a battery of virulence genes in a cascade of regulatory events. The quorum-sensing signal that triggers the cascade is N-3-oxo-dodecanoyl homoserine lactone (3OC12-HSL), which interacts with two signal receptor-transcription factors, LasR and QscR. This signal is base labile, and it is degraded by mammalian PON lactonases. We have identified a structurally unrelated triphenyl mimic of 3OC12-HSL that is base-insensitive and PON-resistant. The triphenyl mimic seems to interact specifically with LasR but not with QscR. In silico analysis suggests that the mimic fits into the 3OC12-HSL-binding site of LasR and makes key contacts with LasR. The triphenyl mimic is an excellent scaffold for developing quorum-sensing inhibitors, and its stability and potency make it ideal for biotechnology uses such as heterologous gene expression.

Exploiting Quorum Sensing To Confuse Bacterial Pathogens

“…For example, the triphenyl signal mimic TP-1 acts as an agonist of LasR and is predicted to form hydrogen bonds with the conserved residues Trp60 and Asp73 in the ligand-binding pocket of the receptor. In contrast, the TP-1-derivative TP-5 (Table 3) is predicted to make only the Asp73 hydrogen bond and instead functions as an antagonist of LasR (125). However, this antagonistic activity could also be the result of predicted steric interference between the third aromatic ring of TP-5 and the ligand-binding pocket, which could induce an aberrant conformation of the receptor (179), and additional structural data will need to be acquired before the precise mechanism of TP-5 antagonism is established.…”

“…However, molecular docking programs have enhanced the ability to predict compounds that would be capable of binding in the ligand-binding pockets of the solved crystal structures or that have two-dimensional (2D) structures similar to those of known agonists or antagonists and thereby would be likely to modulate receptor activity. Such modeling has been utilized by multiple groups and has successfully led to the identification of novel AHL-like and non-AHL-like agonists and antagonists (125,(181)(182)(183)(184). Crystal structures have also helped in the development of reactive QS probes that target LasR.…”

“…Overall, structure-activity relationship (SAR) and molecular modeling studies have indicated that both agonistic and antagonistic interactions require sufficient favorable hydrogen bonding, hydrophobic, and van der Waals interactions between the ligand and ligand-binding site of the receptor to surmount any steric hindrance imposed by the presence of nonnative ligand substituents (125,171,193). This is in agreement with studies demonstrating that even minor changes in the length or substituents of the acyl tail, which contributes to the binding affinity between the receptor and the ligand (11,166,(194)(195)(196), can have large effects on its activity (11,170,197).…”

Crystal structure of QscR, aPseudomonas aeruginosaquorum sensing signal receptor

“…AHL-dependent quorum sensing activates virulence in many plant and animal pathogens, and the LuxR family of AHL receptors has been a target for therapeutic drug development (6)(7)(8)(9)(10)(11)(12). Unfortunately, there is a paucity of structural data for members of the LuxR family of AHL-responsive transcription factors (13).…”

The quorum quenching antibody RS2-1G9 protects macrophages from the cytotoxic effects of the Pseudomonas aeruginosa quorum sensing signalling molecule N-3-oxo-dodecanoyl-homoserine lactone

“…In fact, antivirulence therapies have attracted attraction as a new strategy to combat microbial infections and, thus, bacterial QS represents a promising therapeutic target (Cegelski et al, 2008;Clatworthy et al, 2007). A plethora of small-molecule discovery efforts have been reported (Geske et al, 2007;Hjelmgaard et al, 2003;Muh et al, 2006a;Muh et al, 2006b;Smith et al, 2003). However, our group recently pioneered an immunopharmacotherapeutic approach via the generation of anti-AHL monoclonal antibodies (mAbs) .…”