In vitro and in vivo Evaluation of in silico Predicted Pneumococcal UDPG:PP Inhibitors
| Autor: | Paul Cos, Denis Fourches, Peter Delputte, Nele Geerts, Freya Cools, Dhoha Triki |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Microbiology (medical)
In silico lcsh:QR1-502 Virulence Biology medicine.disease_cause Microbiology lcsh:Microbiology in silico modeling 03 medical and health sciences In vivo Streptococcus pneumoniae medicine Pathogen 030304 developmental biology Original Research GalU 0303 health sciences Innate immune system 030306 microbiology Pharmacology. Therapy Antimicrobial In vitro virulence Galleria mellonella novel drug target |
| Zdroj: | Frontiers in Microbiology Frontiers in Microbiology, Vol 11 (2020) Frontiers in microbiology |
| ISSN: | 1664-302X |
| Popis: | Pneumonia, of which Streptococcus pneumoniae is the most common causative agent, is considered one of the three top leading causes of death worldwide. As seen in other bacterial species, antimicrobial resistance is on the rise for this pathogen. Therefore, there is a pressing need for novel antimicrobial strategies to combat these infections. Recently, uridine diphosphate glucose pyrophosphorylase (UDPG:PP) has been put forward as a potential drug target worth investigating. Moreover, earlier research demonstrated that streptococci lacking a functional galU gene (encoding for UDPG:PP) were characterized by significantly reduced in vitro and in vivo virulence. Therefore, in this study we evaluated the anti-virulence activity of potential UDPG:PP inhibitors. They were selected in silico using a tailor-made streptococcal homology model, based on earlier listerial research. While the compounds didn’t affect bacterial growth, nor affected in vitro adhesion to and phagocytosis in macrophages, the amount of polysaccharide capsule was significantly reduced after co-incubation with these inhibitors. Moreover, co-incubation proved to have a positive effect on survival in an in vivo Galleria mellonella larval infection model. Therefore, rather than targeting bacterial survival directly, these compounds proved to have an effect on streptococcal virulence by lowering the amount of polysaccharide and thereby probably boosting recognition of this pathogen by the innate immune system. While the compounds need adaptation to broaden their activity to more streptococcal strains rather than being strain-specific, this study consolidates UDPG:PP as a potential novel drug target. |
| Databáze: | OpenAIRE |
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