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.
Copyright © 2021 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anti-Bacterial Agents / chemical synthesis*
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Anti-Bacterial Agents / pharmacology
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Antigens, Bacterial / genetics
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Antigens, Bacterial / metabolism
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Bacterial Proteins / genetics*
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Bacterial Proteins / metabolism
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Biological Products
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Caco-2 Cells
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Flagellin / genetics
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Flagellin / metabolism
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Fusaric Acid / analogs & derivatives*
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Fusaric Acid / pharmacology
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Gene Expression Regulation, Bacterial
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Humans
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Microfilament Proteins / genetics
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Microfilament Proteins / metabolism
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Molecular Chaperones / genetics*
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Molecular Chaperones / metabolism
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Salmonella typhimurium / drug effects*
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Salmonella typhimurium / genetics
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Salmonella typhimurium / growth & development
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Salmonella typhimurium / metabolism
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Signal Transduction
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Structure-Activity Relationship
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Transcription Factors / genetics*
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Transcription Factors / metabolism
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Type III Secretion Systems / antagonists & inhibitors*
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Type III Secretion Systems / genetics
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Type III Secretion Systems / metabolism
Substances
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Anti-Bacterial Agents
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Antigens, Bacterial
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Bacterial Proteins
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Biological Products
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DNA-Binding Proteins
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Membrane Proteins
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Microfilament Proteins
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Molecular Chaperones
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Salmonella invasion protein C
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SicA protein, Salmonella typhimurium
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SipA protein, Salmonella
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SspD protein, Salmonella typhimurium
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Transcription Factors
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Type III Secretion Systems
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invF protein, Salmonella
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invasion protein B, Salmonella typhimurium
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Flagellin
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Fusaric Acid