An inhibitor of gram-negative bacterial virulence protein secretion.
Bacterial virulence mechanisms are attractive targets for antibiotic development because they are required for the pathogenesis of numerous global infectious disease agents. The bacterial secretion systems used to assemble the surface structures that promote adherence and deliver protein virulence effectors to host cells could comprise one such therapeutic target. In this study, we developed and performed a high-throughput screen of small molecule libraries and identified one compound, a 2-imino-5-arylidene thiazolidinone that blocked secretion and virulence functions of a wide array of animal and plant Gram-negative bacterial pathogens. This compound inhibited type III secretion-dependent functions, with the exception of flagellar motility, and type II secretion-dependent functions, suggesting that its target could be an outer membrane component conserved between these two secretion systems. This work provides a proof of concept that compounds with a broad spectrum of activity against Gram-negative bacterial secretion systems could be developed to prevent and treat bacterial diseases.
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
Heather B
HB
Felise
Hai V
HV
Nguyen
Richard A
RA
Pfuetzner
Kathleen C
KC
Barry
Stona R
SR
Jackson
Marie-Pierre
MP
Blanc
Philip A
PA
Bronstein
Toni
T
Kline
Samuel I
SI
Miller
D000818:Animals; D000900:Anti-Bacterial Agents / Q000302:isolation & purification / Q000494:pharmacology*; D001422:Bacterial Adhesion / Q000187:drug effects; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D004353:Drug Evaluation, Preclinical; D006090:Gram-Negative Bacteria / Q000187:drug effects* / Q000472:pathogenicity; D008264:Macrophages / Q000382:microbiology; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D018515:Plant Leaves / Q000382:microbiology; D053778:Thiazolidines / Q000302:isolation & purification / Q000494:pharmacology*; D014026:Nicotiana / Q000382:microbiology; D014774:Virulence; D037521:Virulence Factors / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D026901:Membrane Transport Proteins; D053778:Thiazolidines; D037521:Virulence Factors