Rational design and synthesis of new quorum-sensing inhibitors derived from acylated homoserine lactones and natural products from garlic.
Parallel solution-phase synthesis of sulfide AHL analogues (10a-s) by one-pot or a sequential approach is reported. The corresponding sulfoxides 13a-e and sulfones 14a-e were prepared to expand the diversity of the 19-member array of sulfides . Likewise, dithianes 12a-c were prepared with similarity both to sulfides 10a-s and to bioactive structures from garlic. Design and biological screening of all compounds presented in this work targeted inhibition of quorum-sensing comprising competitive inhibition of transcriptional regulators LuxR and LasR. The design was based on critical interactions within the binding-site and structural motifs in molecular components isolated from garlic, 7 and 8, shown to be quorum-sensing inhibitors but not antibiotics. A potent quorum-sensing inhibitor N-(heptylsulfanylacetyl)-l-homoserine lactone (10c) was identified. Together with data collected for the other analogues, the resulting structure-activity relationship led to a hypothesis in which competitive binding was assumed.
Persson
Tobias
T
Department of Natural Sciences, Bioorganic Chemistry Section, Royal Veterinary and Agricultural University, Frederiksberg C, DK-1871, Denmark.
Hansen
Thomas H
TH
Rasmussen
Thomas B
TB
Skindersø
Mette E
ME
Givskov
Michael
M
Nielsen
John
J
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001688:Biological Products / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D005737:Garlic / Q000737:chemistry*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D013329:Structure-Activity Relationship
D001688:Biological Products; C088386:homoserine lactone; D015107:4-Butyrolactone