Structural optimization of natural product fusaric acid to discover novel T3SS inhibitors of Salmonella

Biochem Biophys Res Commun. 2021 Dec 10:582:72-76. doi: 10.1016/j.bbrc.2021.10.035. Epub 2021 Oct 18.

Abstract

Type III secretion system (T3SS) plays a critical role in host cell invasion and pathogenesis of Salmonella. We recently identified the mycotoxin fusaric acid (FA) as a T3SS inhibitor of Salmonella. Herein, twenty-two diphenylsulfane derivatives were designed and synthesized using FA as a lead compound through scaffold hopping. Among them, SL-8 and SL-19 possessing strong anti-T3SS and anti-invasion activity were identified as T3SS inhibitors with improvement in potency as compared to FA. The inhibitory mechanisms on SPI-1 did not depend on the HilD-HilC-RtsA-HilA or PhoP-PhoQ pathway or the assembly of T3SS needle complex. Accordingly, we proposed that the inhibitory effects of SL-8 and SL-19 on SPI-1 probably influence the formation of SicA/InvF-effector complex or other related proteins.

Keywords: Anti-invasion; Diphenylsulfane; Inhibitor; Salmonella; Type III secretion system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / pharmacology
  • Antigens, Bacterial / genetics
  • Antigens, Bacterial / metabolism
  • Bacterial Proteins / genetics*
  • Bacterial Proteins / metabolism
  • Biological Products
  • Caco-2 Cells
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Flagellin / genetics
  • Flagellin / metabolism
  • Fusaric Acid / analogs & derivatives*
  • Fusaric Acid / pharmacology
  • Gene Expression Regulation, Bacterial
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism
  • Molecular Chaperones / genetics*
  • Molecular Chaperones / metabolism
  • Salmonella typhimurium / drug effects*
  • Salmonella typhimurium / genetics
  • Salmonella typhimurium / growth & development
  • Salmonella typhimurium / metabolism
  • Signal Transduction
  • Structure-Activity Relationship
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Type III Secretion Systems / antagonists & inhibitors*
  • Type III Secretion Systems / genetics
  • Type III Secretion Systems / metabolism

Substances

  • Anti-Bacterial Agents
  • Antigens, Bacterial
  • Bacterial Proteins
  • Biological Products
  • DNA-Binding Proteins
  • Membrane Proteins
  • Microfilament Proteins
  • Molecular Chaperones
  • Salmonella invasion protein C
  • SicA protein, Salmonella typhimurium
  • SipA protein, Salmonella
  • SspD protein, Salmonella typhimurium
  • Transcription Factors
  • Type III Secretion Systems
  • invF protein, Salmonella
  • invasion protein B, Salmonella typhimurium
  • Flagellin
  • Fusaric Acid