A natural compound hyperoside targets<i>Salmonella</i>Typhimurium T3SS needle protein InvG

Zhang, Yong; Liu, Yan; Zhang, Bo; Gao, Longnv; Jie, Jing; Deng, Xuming; Liu, Xiaoyun; Sun, Dong; Song, Lei; Luo, Jingjing

doi:10.1039/d2fo00908k

Cited by 5 publications

(1 citation statement)

References 47 publications

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“…Unlike previously reported T3SS-1 inhibitors, such as harmine ( 33 ), tannic acid ( 34 ), and hyperoside ( 35 ), which can significantly improve the survival rates of S. Typhimurium-infected mice, oral administration of S. Typhimurium-challenged mice with fisetin exhibits poor survival phenotype. This might be attributable to its low water solubility ( 36 ), low bioavailability ( 37 ), and poor stability in the intestinal tract ( 38 ).…”

Section: Discussionmentioning

confidence: 80%

Fisetin inhibits Salmonella Typhimurium type III secretion system regulator HilD and reduces pathology in vivo

Li,

Liu,

Shu

et al. 2024

Microbiol Spectr

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Salmonella enterica is an important zoonotic intracellular bacterial pathogen that is capable of causing infections ranging from localized gastroenteritis to fatal systemic infection in humans and food-producing animals. The increasing antibiotic resistance in Salmonella isolates, especially the emergence of MDR and newer XDR strains, has compromised the efficacy of conventional antimicrobial therapy for Salmonella infections. Hence, it is desirable to develop alternative therapeutic means to tackle the antimicrobial resistance crisis. In this study, we screened plant-derived compounds to identify inhibitors of Salmonella invasion of host cells. These efforts identified fisetin as a possible protector against infection. Further mechanistic studies revealed that fisetin suppressed the function of type III secretion system 1 (T3SS-1), the virulence determinant critical for Salmonella invasion. Fisetin appears to interfere with the interaction between HilD and its relevant promoters, thereby decreasing the transcription of hilA , the central transcriptional regulator that functions to activate the expression of T3SS-1 effector proteins and structural elements. In addition, administration of fisetin in the Salmonella murine infection model resulted in reduced bacterial colonization, alleviation of histopathological destruction, and decreased proinflammatory cytokine levels. Taken together, our study establishes that the natural compound fisetin can be used as a lead compound for the development of anti- Salmonella drugs targeting T3SS-1. IMPORTANCE Salmonella spp. remains a major worldwide health concern that causes significant morbidity and mortality in both humans and animals. The spread of antimicrobial resistant strains has declined the efficacy of conventional chemotherapy. Thus, novel anti-infection drugs or strategies are needed. Anti-virulence strategy represents one of the promising means for the treatment of bacterial infections. In this study, we found that the natural compound fisetin could inhibit Salmonella invasion of host cells by targeting SPI-1 regulation. Fisetin treatment impaired the interaction of the regulatory protein HilD with the promoters of its target genes, thereby suppressing the expression of T3SS-1 effectors as well as structural proteins. Moreover, fisetin treatment could reduce pathology in the Salmonella murine infection model. Collectively, our results suggest that fisetin may serve as a promising lead compound for the development of anti-Salmonella drugs.

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Section: Discussionmentioning

confidence: 80%

Fisetin inhibits Salmonella Typhimurium type III secretion system regulator HilD and reduces pathology in vivo

Li,

Liu,

Shu

et al. 2024

Microbiol Spectr

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Application of inhibitors targeting the type III secretion system in phytopathogenic bacteria

He,

Xiong,

Wang

et al. 2024

Chinese Chemical Letters

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Investigation of the inhibitory effect and mechanism of epigallocatechin-3-gallate against Streptococcus suis sortase A

Lou,

Huang,

et al. 2023

Journal of Applied Microbiology

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Aims Streptococcus suis seriously harms people and animals, and importantly, causes great economic losses in the pig industry. Similar to most Gram-positive pathogenic bacteria, sortase A (SrtA) of S. suis can mediate the anchoring of a variety of virulence factors that contain specific sorting sequences to the surface of the bacterial cell wall envelope and participate in pathogenicity. The purpose of this study is to clarify the molecular mechanism of epigallocatechin-3-gallate (EGCG) inhibiting S. suis SrtA and provide more evidence for the development of novel anti-S. suis infections drugs. Methods and results Through the SrtA substrate cleavage experiment, we found that the main component of green tea, EGCG, can effectively inhibit the enzyme activity of S. suis SrtA. Further, molecular docking and molecular dynamics simulation were used to clarify the molecular mechanism of its inhibitory effect, demonstrating that EGCG mainly interacts with amino acids at 113 and 115 to exert its inhibitory function. It was previously found that EGCG can inhibit the growth of S. suis and reduce the activity of suilysin and inhibit its expression. Our research reveals a new function of EGCG in S. suis infection. Conclusions Our research proves that EGCG can effectively inhibit the transpeptidase activity of SrtA. We also clarify the accompanying molecular mechanism, providing more sufficient evidence for the use of EGCG as a potential lead compound against S. suis infection.

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A natural compound hyperoside targetsSalmonellaTyphimurium T3SS needle protein InvG

Abstract: The antimicrobial actions of natural compounds derived from medicinal plants have been well documented. However, their detailed mechanism underlying the action against microorganisms remains largely unexplored. Salmonella enterica is a...

Cited by 5 publications

References 47 publications

Fisetin inhibits Salmonella Typhimurium type III secretion system regulator HilD and reduces pathology in vivo

Fisetin inhibits Salmonella Typhimurium type III secretion system regulator HilD and reduces pathology in vivo

Application of inhibitors targeting the type III secretion system in phytopathogenic bacteria

Investigation of the inhibitory effect and mechanism of epigallocatechin-3-gallate against Streptococcus suis sortase A

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