title: Inhibition of LuxS by S-ribosylhomocysteine analogues containing a [4-aza]ribose ring.
abstract: LuxS (S-ribosylhomocysteinase) catalyzes the cleavage of the thioether linkage of S-ribosylhomocysteine (SRH) to produce homocysteine and 4,5-dihydroxy-2,3-pentanedione (DPD), the precursor to a small signaling molecule that mediates interspecies bacterial communication called autoinducer 2 (AI-2). Inhibitors of LuxS should interfere with bacterial interspecies communication and potentially provide a novel class of antibacterial agents. In this work, SRH analogues containing substitution of a nitrogen atom for the endocyclic oxygen as well as various deoxyriboses were synthesized and evaluated for LuxS inhibition. Two of the [4-aza]SRH analogues showed modest competitive inhibition (K(I) ∼40 μM), while most of the others were inactive. One compound that contains a hemiaminal moiety exhibited time-dependent inhibition, consistent with enzyme-catalyzed ring opening and conversion into a more potent species (K(I)(∗)=3.5 μM). The structure-activity relationship of the designed inhibitors highlights the importance of both the homocysteine and ribose moieties for high-affinity binding to LuxS active site.
authors.affiliation: Department of Chemistry and Biochemistry, Florida International University, Miami, FL 33199, USA.
authors.forename: Venkata L A
authors.initials: VL
authors.lastname: Malladi
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Sobczak
authors.forename: Tiffany M
authors.initials: TM
authors.lastname: Meyer
authors.forename: Dehua
authors.initials: D
authors.lastname: Pei
authors.forename: Stanislaw F
authors.initials: SF
authors.lastname: Wnuk
mesh_terms: D001412:Bacillus subtilis / Q000201:enzymology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013437:Carbon-Sulfur Lyases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006710:Homocysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D012266:Ribose / Q000031:analogs & derivatives / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D001426:Bacterial Proteins; C487472:S-ribosyl-L-homocysteine; D006710:Homocysteine; D012266:Ribose; D013437:Carbon-Sulfur Lyases; C117753:LuxS protein, Bacteria