Tethered thiazolidinone dimers as inhibitors of the bacterial type III secretion system.
Disruption of protein-protein interactions by small molecules is achievable but presents significant hurdles for effective compound design. In earlier work we identified a series of thiazolidinone inhibitors of the bacterial type III secretion system (T3SS) and demonstrated that this scaffold had the potential to be expanded into molecules with broad-spectrum anti-Gram negative activity. We now report on one series of thiazolidinone analogs in which the heterocycle is presented as a dimer at the termini of a series of linkers. Many of these dimers inhibited the T3SS-dependent secretion of a virulence protein at concentrations lower than that of the original monomeric compound identified in our screen.
Kline
Toni
T
Department of Immunology, University of Washington, Seattle, WA 98195, USA.
Barry
Kathleen C
KC
Jackson
Stona R
SR
Felise
Heather B
HB
Nguyen
Hai V
HV
Miller
Samuel I
SI
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D055571:Secretory Pathway / Q000187:drug effects / Q000502:physiology*; D045162:Thiazolidinediones / Q000138:chemical synthesis* / Q000494:pharmacology; D000069296:Type III Secretion Systems; D014774:Virulence / Q000187:drug effects / Q000502:physiology
D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; C114344:PAS protein, E coli; D045162:Thiazolidinediones; D000069296:Type III Secretion Systems