Small-molecule AgrA inhibitors F12 and F19 act as antivirulence agents against Gram-positive pathogens
| العنوان: | Small-molecule AgrA inhibitors F12 and F19 act as antivirulence agents against Gram-positive pathogens |
|---|---|
| المؤلفون: | David Kuo, Kiran Bandi, Lisa Long, Yaron Shoham, Divya Manoharan, Danyang Ma, Mahmoud A. Ghannoum, Eckhard Jankowsky, Michael Greenberg, Menachem Shoham, Chris Hager, William E. Harte |
| المصدر: | Scientific Reports, Vol 8, Iss 1, Pp 1-12 (2018) Scientific Reports |
| بيانات النشر: | Nature Publishing Group, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, medicine.drug_class, Virulence Factors, medicine.medical_treatment, 030106 microbiology, Antibiotics, lcsh:Medicine, Biology, medicine.disease_cause, Gram-Positive Bacteria, Article, Microbiology, Sepsis, 03 medical and health sciences, Mice, Bacterial Proteins, In vivo, medicine, Animals, lcsh:Science, Transcription factor, Multidisciplinary, Virulence, Toxin, lcsh:R, Drug Synergism, Staphylococcal Infections, biology.organism_classification, medicine.disease, Survival Analysis, In vitro, Anti-Bacterial Agents, Disease Models, Animal, 030104 developmental biology, Treatment Outcome, Trans-Activators, Wound Infection, lcsh:Q, Adjuvant, Bacteria |
| الوصف: | Small-molecule antivirulence agents represent a promising alternative or adjuvant to antibiotics. These compounds disarm pathogens of disease-causing toxins without killing them, thereby diminishing survival pressure to develop resistance. Here we show that the small-molecule antivirulence agents F12 and F19 block staphylococcal transcription factor AgrA from binding to its promoter. Consequently, toxin expression is inhibited, thus preventing host cell damage by Gram-positive pathogens. Broad spectrum efficacy against Gram-positive pathogens is due to the existence of AgrA homologs in many Gram-positive bacteria. F12 is more efficacious in vitro and F19 works better in vivo. In a murine MRSA bacteremia/sepsis model, F19 treatment alone resulted in 100% survival while untreated animals had 70% mortality. Furthermore, F19 enhances antibiotic efficacy in vivo. Notably, in a murine MRSA wound infection model, combination of F19 with antibiotics resulted in bacterial load reduction. Thus, F19 could be used alone or in combination with antibiotics to prevent and treat infections of Gram-positive pathogens. |
| اللغة: | English |
| تدمد: | 2045-2322 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::de77e4ef0eb87a8e3c66235e5cbbbdf1Test http://link.springer.com/article/10.1038/s41598-018-32829-wTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....de77e4ef0eb87a8e3c66235e5cbbbdf1 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20452322 |
|---|