Novel inhibitor discovery and the conformational analysis of inhibitors of listeriolysin O via protein-ligand modeling

Wang, Jianfeng; Zhou, Xuan; Shui, Lingling; Li, Gen; Zhang, Bing; Deng, Xuming; Niu, Xiaodi

doi:10.1038/srep08864

Cited by 26 publications

(40 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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%

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.

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

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.

Self Cite

View full text Add to dashboard Cite

show abstract

“…The starting structure of the ligand/srtA complex for the molecular dynamics (MD) simulation was obtained using AutoDock 4 based on the standard docking procedure for a rigid protein and a flexible ligand. Then, the MD simulation was carried out for the complex using detailed computational biological processes described in previous reports …”

Section: Methodsmentioning

confidence: 99%

“…Then, the MD simulation was carried out for the complex using detailed computational biological processes described in previous reports. 23…”

Section: Molecular Modellingmentioning

confidence: 99%

Quercetin impairs Streptococcus pneumoniae biofilm formation by inhibiting sortase A activity

Wang

Meng

Pan

et al. 2018

J Cellular Molecular Medi

Self Cite

View full text Add to dashboard Cite

Biofilm formation mediated by sortase A (srtA) is important for bacterial colonisation and resistance to antibiotics. Thus, the inhibitor of SrtA may represent a promising agent for bacterial infection. The structure of Streptococcus pneumoniae D39 srtA has been characterised by crystallisation. Site‐directed mutagenesis was used for the determination of the key residues for the activity of S. pneumoniae D39 srtA. An effective srtA inhibitor, quercetin, and its mechanism was further identified using srtA activity inhibition assay and molecular modelling. In this study, the crystal structure of S. pneumoniae D39 srtA has been solved and shown to contain a unique domain B. Additionally, its transpeptidase activity was evaluated in vitro. Based on the structure, we identified Cys207 as the catalytic residue, with His141 and Arg215 serving as binding sites for the peptide substrate. We found that quercetin can specifically compete with the natural substrate, leading to a significant decrease in the catalytic activity of this enzyme. In cells co‐cultured with this small molecule inhibitor, NanA cannot anchor to the cell wall effectively, and biofilm formation and biomass decrease significantly. Interestingly, when we supplemented cultures with sialic acid, a crucial signal for pneumococcal coloniation and the invasion of the host in the co‐culture system, biofilm loss did not occur. This result indicates that quercetin inhibits biofilm formation by affecting sialic acid production. In conclusion, the inhibition of pneumococcal srtA by the small molecule quercetin offers a novel strategy for pneumococcal preventative therapy.

show abstract

“…The myricetin (Figure 8H) is a compound able to interact with listeriolysin O, a virulence factor of Listeria monocytogenes that is involved in the lysis of host cells. This interaction is related to the presence of the double bond in the molecule, specifically in the C1-C2 position in ring C [99]. This generates a complex that blocks the hemolytic activity of the listeriolysin as it prevents binding to cholesterol.…”

Section: Quercetin and Related Compoundsmentioning

confidence: 99%

Phenolic Compounds with Anti-virulence Properties

Muñoz-Cázares¹,

García‐Contreras²,

López³

et al. 2017

Phenolic Compounds - Biological Activity

View full text Add to dashboard Cite

Natural products represent the major source of approved drugs and still play an important role in supplying chemical diversity as well as new structures for designing more efficient antimicrobials. They are also the basis for the discovery of new mechanisms of antibacterial action. In this regard, a large number of substances, mainly extracts from natural sources, have been obtained in order to identify their anti-virulence activity. In recent years, there is an increase in the study of anti-virulence natural product derivatives. Different targets have been proposed as a solution to the serious problem of bacterial antibiotic resistance. Inhibition of bacterial quorum-sensing systems has been one of the most studied; however, there are other mechanisms involved in virulence regulation, damage to the host and bacterial survival, which suggests that there are another good targets such as bacterial secretion systems, biofilm formation, two-component systems, flagellum, fimbriae, toxins and key enzymes. Within the natural products, the main anti-virulence compounds are phenolic in nature, so that the next chapter describes and analyzes the relationship between chemical structure and activity of the main phenolic compounds reported.

show abstract

Novel inhibitor discovery and the conformational analysis of inhibitors of listeriolysin O via protein-ligand modeling

Cited by 26 publications

References 25 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

Quercetin impairs Streptococcus pneumoniae biofilm formation by inhibiting sortase A activity

Phenolic Compounds with Anti-virulence Properties

Contact Info

Product

Resources

About