دورية أكاديمية
Biosynthesis of Aurodox, a Type III Secretion System Inhibitor from Streptomyces goldiniensis.
| العنوان: | Biosynthesis of Aurodox, a Type III Secretion System Inhibitor from Streptomyces goldiniensis. |
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| المؤلفون: | McHugh RE; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclydegrid.11984.35, Glasgow, UK.; Institute of Infection, Immunity and Inflammation, University of Glasgowgrid.8756.c, Glasgow, UK., Munnoch JT; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclydegrid.11984.35, Glasgow, UK., Braes RE; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclydegrid.11984.35, Glasgow, UK., McKean IJW; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclydegrid.11984.35, Glasgow, UK.; Department of Pure and Applied Chemistry, University of Strathclydegrid.11984.35, Glasgow, UK., Giard J; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclydegrid.11984.35, Glasgow, UK., Taladriz-Sender A; Department of Pure and Applied Chemistry, University of Strathclydegrid.11984.35, Glasgow, UK., Peschke F; Department of Pure and Applied Chemistry, University of Strathclydegrid.11984.35, Glasgow, UK., Burley GA; Department of Pure and Applied Chemistry, University of Strathclydegrid.11984.35, Glasgow, UK., Roe AJ; Institute of Infection, Immunity and Inflammation, University of Glasgowgrid.8756.c, Glasgow, UK., Hoskisson PA; Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclydegrid.11984.35, Glasgow, UK. |
| المصدر: | Applied and environmental microbiology [Appl Environ Microbiol] 2022 Aug 09; Vol. 88 (15), pp. e0069222. Date of Electronic Publication: 2022 Jul 18. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Microbiology Country of Publication: United States NLM ID: 7605801 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1098-5336 (Electronic) Linking ISSN: 00992240 NLM ISO Abbreviation: Appl Environ Microbiol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, American Society for Microbiology. |
| مواضيع طبية MeSH: | Aurodox*/pharmacology , Streptomyces*/genetics, Anti-Bacterial Agents/pharmacology ; Multigene Family ; Polyketide Synthases/genetics ; Type III Secretion Systems |
| مستخلص: | The global increase in antimicrobial-resistant infections means that there is a need to develop new antimicrobial molecules and strategies to combat the issue. Aurodox is a linear polyketide natural product that is produced by Streptomyces goldiniensis, yet little is known about aurodox biosynthesis or the nature of the biosynthetic gene cluster (BGC) that encodes its production. To gain a deeper understanding of aurodox biosynthesis by S. goldiniensis, the whole genome of the organism was sequenced, revealing the presence of an 87 kb hybrid polyketide synthase/non-ribosomal peptide synthetase (PKS/NRPS) BGC. The aurodox BGC shares significant homology with the kirromycin BGC from S. collinus Tϋ 365. However, the genetic organization of the BGC differs significantly. The candidate aurodox gene cluster was cloned and expressed in a heterologous host to demonstrate that it was responsible for aurodox biosynthesis and disruption of the primary PKS gene ( aurAI ) abolished aurodox production. These data supported a model whereby the initial core biosynthetic reactions involved in aurodox biosynthesis followed that of kirromycin. Cloning aurM* from S. goldiniensis and expressing this in the kirromycin producer S. collinus Tϋ 365 enabled methylation of the pyridone group, suggesting this is the last step in biosynthesis. This methylation step is also sufficient to confer the unique type III secretion system inhibitory properties to aurodox. IMPORTANCE Enterohemorrhagic Escherichia coli (EHEC) is a significant global pathogen for which traditional antibiotic treatment is not recommended. Aurodox inhibits the ability of EHEC to establish infection in the host gut through the specific targeting of the type III secretion system while circumventing the induction of toxin production associated with traditional antibiotics. These properties suggest aurodox could be a promising anti-virulence compound for EHEC, which merits further investigation. Here, we characterized the aurodox biosynthetic gene cluster from Streptomyces goldiniensis and established the key enzymatic steps of aurodox biosynthesis that give rise to the unique anti-virulence activity. These data provide the basis for future chemical and genetic approaches to produce aurodox derivatives with increased efficacy and the potential to engineer novel elfamycins. |
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| معلومات مُعتمدة: | BB/T001038/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; BB/T004126/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; MR/V011499/1 United Kingdom MRC_ Medical Research Council |
| فهرسة مساهمة: | Keywords: EHEC; Streptomyces; antibiotic; aurodox; biosynthesis; elfamycin; kirromycin; polyketide |
| سلسلة جزيئية: | figshare 10.6084/m9.figshare.19140005.v1 |
| المشرفين على المادة: | 0 (Anti-Bacterial Agents) 0 (Type III Secretion Systems) 12704-90-4 (Aurodox) 79956-01-7 (Polyketide Synthases) |
| تواريخ الأحداث: | Date Created: 20220722 Date Completed: 20220811 Latest Revision: 20231105 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC9361827 |
| DOI: | 10.1128/aem.00692-22 |
| PMID: | 35867559 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1098-5336 |
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| DOI: | 10.1128/aem.00692-22 |