Structure‐Based Discovery and Experimental Verification of Novel AI‐2 Quorum Sensing Inhibitors against Vibrio harveyi

Abstract

Quorum sensing has been implicated in the control of pathologically relevant bacterial behavior such as secretion of virulence factors, biofilm formation, sporulation, and swarming motility. The AI-2 quorum sensing pathway is found in both gram-positive and gram-negative bacteria. Therefore, antagonizing AI-2 quorum sensing is a possible approach to modifying bacterial behaviour. However, efforts in developing inhibitors of AI-2-mediated quorum sensing are especially lacking. High-throughput virtual screening using the V. harveyi LuxP crystal structure identified two compounds that were found to antagonize AI-2-mediated quorum sensing in V. harveyi without cytotoxicity. The sulfone functionality of these inhibitors was identified as critical to their ability to mimic the natural ligand in their interactions with Arg 215 and Arg 310 of the active site.

Chemical Validation of Phosphodiesterase C as a Chemotherapeutic Target in Trypanosoma cruzi , the Etiological Agent of Chagas' Disease

“…Then, AM1-BCC partial charges were assigned (13,14,33). This docking-based virtual screening was conducted by following procedures similar to those we reported elsewhere (18,19). The position and conformation of each compound were optimized first by the anchor fragment orientation and then by the torsion minimization method implemented in the DOCK 6 software program (8,23).…”

“…In order to search for additional PDEC inhibitors, we used the homology model (see Fig. S2A in the supplemental material) and conducted virtual screening against the Maybridge database, containing about 60,000 compounds, using the DOCK 6 program, following procedures described in earlier publications (18,19,33). Twenty-five compounds were identified for biological evaluation.…”

Exploiting Quorum Sensing To Confuse Bacterial Pathogens

“…With the concept of molecular mimicry in hand and the goal of identifying novel antagonists of AI-2 signaling, Wang and colleagues published a series of papers in which they screened a large number of compounds that they believed would have the potential to complex with the V. harveyi receptor LuxP (131,204,205). They chose to focus on compounds with molecular structures significantly different from those of the previously examined nonaromatic cyclic polyols which generally exhibited agonist activity (206)(207)(208).…”

“…2) (35, 36). The third screen tested approximately 1.7 million compounds from commercial compound databases by in silico analysis against the LuxP-AI-2 holoform crystal structure (204). These three screens yielded a total of 12 AI-2 QS inhibitors with 50% inhibitory concentrations (IC 50 s) in the micromolar range (single-digit micromolar range for the 10 compounds identified in the first two screens) in whole-cell assays with V. harveyi, without significant effects on bacterial growth.…”

Modification of quorum sensing in bacterial cultures

“…Pyrogallol is probably the best inhibitor, but different DPD analogues also have a great future (86)(87)(88).…”