Inhibition of sortase A by chalcone prevents Listeria monocytogenes infection

Li, Hongen; Zhang, Bing; Niu, Xiaodi; Meng, Shaoping; Luo, Zhao‐Qing; Lu, Gejin; Liu, Bowen; Zhao, Xiaoru; Wang, Jianfeng; Deng, Xuming

doi:10.1016/j.bcp.2016.01.018

Cited by 37 publications

(37 citation statements)

References 36 publications

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“…In agreement with this idea, in previous works, we significantly decreased the pathogenicity of L. monocytogenes both in vitro and in vivo by targeting LLO or SrtA using treatments with natural compounds (Wang et al, 2015a; Li et al, 2016). We therefore reasoned that a better anti-infective therapeutic effect may be observed using an inhibitor that simultaneously targets both LLO and SrtA.…”

Section: Introductionsupporting

confidence: 89%

“…Potential inhibitors of L. monocytogenes virulence factors were identified using a phenotypic assay based on protein function (Wang et al, 2015a,b; Li et al, 2016). In this work, the hemolytic activities of culture supernatants of L. monocytogenes EGDe cells dose-dependently decreased after co-culture with various concentrations of phloretin (7.3–58.34 μM) (Figures 1A,B).…”

Section: Resultsmentioning

confidence: 99%

“…Cell-surface proteins containing the peptide motif LPXTG are linked to cell walls by SrtA and facilitate L. monocytogenes invasion into host cells (Li et al, 2016). Following internalization, secreted LLO facilitates L. monocytogenes escape from internalization vacuoles into cytoplasm by lysing biomembranes (Hamon et al, 2012).…”

Section: Resultsmentioning

confidence: 99%

“…Expression vectors for SrtA mutants (SrtA T90A, SrtA I103A, and V129A) were constructed using a QuikChange site-directed mutagenesis kit (Stratagene, La Jolla, CA, USA) based on the SrtAΔN70-pGEX-6P-1 construct, a vector created in our lab for the expression of wild type SrtA (WT-SrtA) (Li et al, 2016). The primer pairs for these three mutations were as follows: T90A forward, 5′-GAATATACAGTTGCGGAAACAAAAAC-3′; T90A reverse, 5′-GTTTTTGTTTCCGCAACTGTATATTC-3′; I103A forward, 5′-GATGAAACAGAAGTAAGCGTTGCGGATAATACGAAAGATGCTAG-3′; I103A reverse, 5′-CTAGCATCTTTCGTATTATCCGCAACGCTTACTTCTGTTTCATC-3′; V129A forward, 5′-GAAACGTTTTGTCGCAGCGGGTGAGCTAGAAAAAAC-3′; and V129A reverse, 5′-GTTTTTTCTAGCTCACCCGCTGCGACAAAACGTTTC-3′.…”

Section: Methodsmentioning

confidence: 99%

“…The primer pairs for these three mutations were as follows: T90A forward, 5′-GAATATACAGTTGCGGAAACAAAAAC-3′; T90A reverse, 5′-GTTTTTGTTTCCGCAACTGTATATTC-3′; I103A forward, 5′-GATGAAACAGAAGTAAGCGTTGCGGATAATACGAAAGATGCTAG-3′; I103A reverse, 5′-CTAGCATCTTTCGTATTATCCGCAACGCTTACTTCTGTTTCATC-3′; V129A forward, 5′-GAAACGTTTTGTCGCAGCGGGTGAGCTAGAAAAAAC-3′; and V129A reverse, 5′-GTTTTTTCTAGCTCACCCGCTGCGACAAAACGTTTC-3′. The expression and purification of WT-SrtA and its derivatives was carried out as described in our previous study (Li et al, 2016). …”

Section: Methodsmentioning

confidence: 99%

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Phloretin Attenuates Listeria monocytogenes Virulence Both In vitro and In vivo by Simultaneously Targeting Listeriolysin O and Sortase A

Wang

Liu

Teng

et al. 2017

Front. Cell. Infect. Microbiol.

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The critical roles of sortase A (SrtA) and listeriolysin O (LLO) in Listeria monocytogenes pathogenicity render these two virulence factors as ideal targets for the development of anti-virulence agents against L. monocytogenes infection. Additionally, the structures of SrtA and LLO are highly conserved among the members of sortase enzyme family and cholesterol dependent toxin family. Here, phloretin, a natural polyphenolic compound derived from apples and pears that has little anti-L. monocytogenes activity, was identified to simultaneously inhibit LLO expression and neutralize SrtA catalytic activity. Phloretin neutralized SrtA activity by causing a conformational change in the protein's active pocket, which prevented engagement with its substrate. Treatment with phloretin simultaneously reduced L. monocytogenes invasion into host cells and blocked the escape of vacuole-entrapped L. monocytogenes into cytoplasm. Further, L. monocytogenes-infected mice that received phloretin showed lower mortality, decreased bacterial burden and reduced pathological injury. Our results demonstrate that phloretin is a promising anti-infective therapeutic for infections caused by L. monocytogenes due to its simultaneous targeting of SrtA and LLO, which may result in fewer side effects than those caused by other antibiotics.

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Section: Introductionsupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Phloretin Attenuates Listeria monocytogenes Virulence Both In vitro and In vivo by Simultaneously Targeting Listeriolysin O and Sortase A

Wang

Liu

Teng

et al. 2017

Front. Cell. Infect. Microbiol.

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Nutraceuticals and Natural‐Product Derivatives for Disease Prevention

Taneja

Singh

Shivaprasad

et al. 2022

Handbook of Nutraceuticals and Natural Products

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An idea to explore: Engaging high school students in structure‐function studies of bacterial sortase enzymes and inhibitors ‐ A comprehensive computational experimental pipeline

Godse,

Sapar,

Amacher

2023

Biochem Molecular Bio Educ

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High school science fairs provide an exceptional opportunity for students to gain experience with scientific research, and participation has positive outcomes with respect to chosen careers in the sciences. However, it can be challenging to engage high school students in university‐level research outside of formal internship programs. Here, we describe an experimental pipeline for a computational structural biology project that engages high school students. Students are involved at every step of the investigation and utilize freely available software to dock inhibitors onto protein homologues, and then analyze the resulting complexes. Bacterial sortases are transpeptidases on the cell surface of Gram‐positive bacteria and are a potential target for the development of antibiotics. Students modeled inhibitors bound to sortases from several organisms, asking questions about affinity and selectivity. Their project was ranked in the top 10% at both regional and state science fairs. This project design is easily adaptable to countless other protein systems and provides a pipeline for collaborative high school student/university professor inquiry.

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Inhibition of sortase A by chalcone prevents Listeria monocytogenes infection

Cited by 37 publications

References 36 publications

Phloretin Attenuates Listeria monocytogenes Virulence Both In vitro and In vivo by Simultaneously Targeting Listeriolysin O and Sortase A

Phloretin Attenuates Listeria monocytogenes Virulence Both In vitro and In vivo by Simultaneously Targeting Listeriolysin O and Sortase A

Nutraceuticals and Natural‐Product Derivatives for Disease Prevention

An idea to explore: Engaging high school students in structure‐function studies of bacterial sortase enzymes and inhibitors ‐ A comprehensive computational experimental pipeline

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