Small molecules for interference with cell-cell-communication systems in Gram-negative bacteria.
Quorum sensing (QS) systems are bacterial cell-to-cell communication systems that use small molecules as signals. Since QS is involved in the regulation of virulence and biofilm formation in several pathogenic bacteria, it has been suggested as a new target for the development of novel antibacterial therapies. As such, interference with the signal receptors by using chemical compounds has been proposed as an alternative strategy for treatment of bacterial infections and has already shown promising results in combination with traditional antibiotic treatments. In Gram-negative bacteria, the best studied QS systems use N-acyl homoserine lactones (AHLs) as signal molecules. This review provides an overview of all new chemical structure types that inhibit AHL-mediated QS systems as reported during the last three years in scientific journals and in the patent literature. The compounds were classified into three main groups depending on their structure: AHL analogues, 2(5H)-furanones, and compounds that are not structurally related to AHLs. We discuss the biological assays used and the different strategies applied to discover these molecules, including new approaches such as molecular docking for in silico identification of lead structures and random high-throughput screening of large libraries of chemicals. Finally, we elaborate on structure-activity relationships and on the new insights in the mechanisms of action of the identified inhibitors, highlighting the potential of these small molecules in medicine.
Janssens
Joost C A
JC
Department of Microbial and Molecular Systems, Centre of Microbial and Plant Genetics, K. U. Leuven, Kasteelpark Arenberg 20, B-3001 Leuven, Belgium.
De Keersmaecker
Sigrid C J
SC
De Vos
Dirk E
DE
Vanderleyden
Jos
J
D054742:Acyl-Butyrolactones / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000166:cytology* / Q000187:drug effects* / Q000502:physiology; D015394:Molecular Structure; D008970:Molecular Weight; D053038:Quorum Sensing / Q000187:drug effects*; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D054742:Acyl-Butyrolactones; D000900:Anti-Bacterial Agents; D054852:Small Molecule Libraries