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Conference Paper: Disarming the protective pigments of Staphylococcus aureus by a small molecule compound

TitleDisarming the protective pigments of Staphylococcus aureus by a small molecule compound
Authors
Issue Date2017
PublisherInternational Chemical Biology Society.
Citation
The 6th Official Conference of the International Chemical Biology Society (ICBS) 2017, Shanghai, China, 17-20 October 2017 How to Cite?
AbstractIntroduction: Staphylococcus aureus, especially methicillin-resistant S. aureus (MRSA), is a life-threatening pathogen in hospital- and community-acquired infections. The golden-coloured carotenoid pigment of S. aureus, staphyloxanthin, contributes substantially to pathogenesis by interfering with host immune clearance mechanisms but has negligible impact on ex vivo survival of the bacteria. Agents blocking staphyloxanthin production may discourage the establishment and maintenance of bacterial infection without exerting selective pressure for antimicrobial resistance. Materials & Methods: The inhibition of S. aureus pigment production by a small molecule compound (NP16) was conducted by measuring the absorbance of extracted bacterial carotenoids. To investigate the potential target of NP16, enzymatic assays of two key enzymes in staphyloxanthin biosynthesis pathway, dehydrosqualene synthase (CrtM) and dehydrosqualene desaturase (CrtN), were performed to evaluate the inhibitory effects of NP16. Carotenoids analysis by LC/Ms was further employed to trace various pigment intermediates in the presence of NP16 and the effect of NP16 on the survival of S. aureus in neutrophil or in the presence of H2O2 was also evaluated. Furthermore, the crtN deleted and overexpressed S. aureus were used to address the specificity of NP16 inhibition. Finally, the efficacies of NP16 on animal infection models were investigated. Results, Discussion & Conclusion: NP16 showed inhibition against CrtN rather than CrtM and had no effect on the expression level of the two genes. NP16 treatment led to the accumulation of 4,4’-diapophytoene, the substrate of CrtN, indicating the target of NP16 should be CrtN. Mutational studies further support the conclusion that the molecular target of NP16 is CrtN. NP16 treated S. aureus has led to increased susceptibility of the bacteria to H2O2 and human neutrophil killing. However, the presence of NP16 didn’t affect the susceptibility of crtN deleted S. aureus, indicating NP16 is a specific inhibitor of CrtN. In mouse infection models, NP16 significantly decreased the staphylococcal loads in the spleens, livers and kidneys. Our study validated CrtN as a novel druggable target in S. aureus and identified a potent and effective lead compound for potential development of virulence factor-based therapy against S. aureus.
Persistent Identifierhttp://hdl.handle.net/10722/259730

 

DC FieldValueLanguage
dc.contributor.authorGao, P-
dc.contributor.authorKao, RYT-
dc.date.accessioned2018-09-03T04:12:59Z-
dc.date.available2018-09-03T04:12:59Z-
dc.date.issued2017-
dc.identifier.citationThe 6th Official Conference of the International Chemical Biology Society (ICBS) 2017, Shanghai, China, 17-20 October 2017-
dc.identifier.urihttp://hdl.handle.net/10722/259730-
dc.description.abstractIntroduction: Staphylococcus aureus, especially methicillin-resistant S. aureus (MRSA), is a life-threatening pathogen in hospital- and community-acquired infections. The golden-coloured carotenoid pigment of S. aureus, staphyloxanthin, contributes substantially to pathogenesis by interfering with host immune clearance mechanisms but has negligible impact on ex vivo survival of the bacteria. Agents blocking staphyloxanthin production may discourage the establishment and maintenance of bacterial infection without exerting selective pressure for antimicrobial resistance. Materials & Methods: The inhibition of S. aureus pigment production by a small molecule compound (NP16) was conducted by measuring the absorbance of extracted bacterial carotenoids. To investigate the potential target of NP16, enzymatic assays of two key enzymes in staphyloxanthin biosynthesis pathway, dehydrosqualene synthase (CrtM) and dehydrosqualene desaturase (CrtN), were performed to evaluate the inhibitory effects of NP16. Carotenoids analysis by LC/Ms was further employed to trace various pigment intermediates in the presence of NP16 and the effect of NP16 on the survival of S. aureus in neutrophil or in the presence of H2O2 was also evaluated. Furthermore, the crtN deleted and overexpressed S. aureus were used to address the specificity of NP16 inhibition. Finally, the efficacies of NP16 on animal infection models were investigated. Results, Discussion & Conclusion: NP16 showed inhibition against CrtN rather than CrtM and had no effect on the expression level of the two genes. NP16 treatment led to the accumulation of 4,4’-diapophytoene, the substrate of CrtN, indicating the target of NP16 should be CrtN. Mutational studies further support the conclusion that the molecular target of NP16 is CrtN. NP16 treated S. aureus has led to increased susceptibility of the bacteria to H2O2 and human neutrophil killing. However, the presence of NP16 didn’t affect the susceptibility of crtN deleted S. aureus, indicating NP16 is a specific inhibitor of CrtN. In mouse infection models, NP16 significantly decreased the staphylococcal loads in the spleens, livers and kidneys. Our study validated CrtN as a novel druggable target in S. aureus and identified a potent and effective lead compound for potential development of virulence factor-based therapy against S. aureus.-
dc.languageeng-
dc.publisherInternational Chemical Biology Society. -
dc.relation.ispartofThe Official Conference of the International Chemical Biology Society (ICBS) -
dc.titleDisarming the protective pigments of Staphylococcus aureus by a small molecule compound-
dc.typeConference_Paper-
dc.identifier.emailGao, P: gaopeng@hku.hk-
dc.identifier.emailKao, RYT: rytkao@hkucc.hku.hk-
dc.identifier.authorityKao, RYT=rp00481-
dc.identifier.hkuros287779-
dc.publisher.placeShanghai, China-

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