Comparative analyses of N-acylated homoserine lactones reveal unique structural features that dictate their ability to activate or inhibit quorum sensing

Abstract

Bacterial quorum sensing is mediated by low molecular-weight signals and plays a critical role in both the pathogenesis of infectious disease and beneficial symbioses. There is significant interest in the development of synthetic ligands that can intercept bacterial quorum sensing signals and modulate these outcomes. Here, we report the design and comparative analysis of the effects of approximately 90 synthetic N-acylated homoserine lactones (AHLs) on quorum sensing in three Gram negative bacterial species and a critical examination of the structural features of these ligands that dictate agonistic and antagonistic activity, and selectivity for different R protein targets. These studies have revealed the most comprehensive set of structure-activity relationships to date that direct AHL-mediated quorum sensing and a new set of chemical probes with which to study this complex signaling process. Furthermore, this work provides a foundation on which to design next-generation quorum sensing modulators with improved activities and selectivities.

Figure 1

Pharmacophore models for AHL modulators of A) TraR, B) LasR, and C) LuxR calculated from primary screening data for libraries A–D. Green represents hydrophobic/aromatic features, red represents hydrogen-bond donor features, and orange represents hydrogen-bond acceptor features of the pharmacophore. Each pharmacophore is depicted with a selected set of active AHLs to highlight the varying features between the three pharmacophore models: OOHL (1), A11, C10, and D6 for TraR, OdDHL (2), C10, C14, and D18 for LasR, and OHHL (3), C6, C10, and C14 for LuxR.

Scheme 1

Generic structure of an N-acylated l-homoserine lactone (AHL), and structures of selected native AHL ligands (1–3) and known synthetic antagonists of R protein function (4–9). The number of carbon atoms (C) in selected aliphatic acyl groups is indicated for clarity.

Scheme 2

Structures of AHL libraries A–D. The number of carbon atoms (C) in certain aliphatic acyl groups is indicated for clarity. **=Indicates the AHL has d-stereochemistry; all others have l-stereochemistry.