Pharmacological inhibition of quorum sensing for the treatment of chronic bacterial infections

Abstract

Traditional treatment of infectious diseases is based on compounds that aim to kill or inhibit bacterial growth. A major concern with this approach is the frequently observed development of resistance to antimicrobial compounds. The discovery of bacterial-communication systems (quorum-sensing systems), which orchestrate important temporal events during the infection process, has afforded a novel opportunity to ameliorate bacterial infection by means other than growth inhibition. Compounds able to override bacterial signaling are present in nature. Herein we discuss the known signaling mechanisms and potential antipathogenic drugs that specifically target quorum-sensing systems in a manner unlikely to pose a selective pressure for the development of resistant mutants.

Figure 1

The archetypical Lux quorum sensor. The AHL signal (green circles) is synthesized by the luxI gene product LuxI (the synthase). At a certain threshold concentration, the AHL signal interacts with the receptor LuxR (encoded by luxR), which binds to the promoter sequence of the target genes (in this case, the lux operon) and in conjunction with the RNA polymerase promotes transcription.

Figure 2

(a) Molecular structures of the two cognate signal molecules produced by P. aeruginosa, BHL ([N-butyryl]-L-homoserine lactone), and OdDHL (N-[3-oxo-dodecanoyl]-L-homoserine lactone). (b) Synthetic quorum-sensing (QS) inhibitors derived from (c) natural brominated furanone compounds isolated from D. pulchra. (d) Temporal biofilm development and dispersal. Stars represent QS.

Figure 3

Furanone-treated P. aeruginosa biofilms are less tolerant to tobramycin. Scanning confocal laser photomicrographs of P. aeruginosa PAO1 biofilms grown in the absence (a) or the presence (b) of 10 μM C-30. After 3 days, the biofilms were exposed to 100 μg/ml tobramycin for 24 hours. Bacterial viability was assayed by staining using the LIVE/DEAD BacLight Bacterial Viability Kit (Molecular Probes Inc., Eugene, Oregon, USA). Red areas are dead bacteria; green areas are live bacteria.