Discovery and Biosynthesis of Gladiolin: A Burkholderia gladioli Antibiotic with Promising Activity against Mycobacterium tuberculosis
| العنوان: | Discovery and Biosynthesis of Gladiolin: A Burkholderia gladioli Antibiotic with Promising Activity against Mycobacterium tuberculosis |
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| المؤلفون: | Matthew J. Bull, Cerith Jones, Stewart T. Cole, Eshwar Mahenthiralingam, C. Paisey, Gregory L. Challis, Joleen Masschelein, Anthony Vocat, Simon R. Harris, Julian Parkhill, Lijiang Song, Paul Coupland, Isolda Romero-Canelón, Gordon Webster, Matthew Jenner, Matthew Dunn, Ruben C. Hartkoorn, Rebecca Weiser |
| المساهمون: | Parkhill, Julian [0000-0002-7069-5958], Apollo - University of Cambridge Repository |
| المصدر: | Journal of the American Chemical Society. 139:7974-7981 |
| بيانات النشر: | American Chemical Society (ACS), 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Burkholderia gladioli, Tuberculosis, medicine.drug_class, 030106 microbiology, Antibiotics, Molecular Conformation, Microbial Sensitivity Tests, 01 natural sciences, Biochemistry, Catalysis, Microbiology, Mycobacterium tuberculosis, Structure-Activity Relationship, 03 medical and health sciences, Colloid and Surface Chemistry, Drug Discovery, medicine, Enzyme Inhibitors, Sorangium cellulosum, Dose-Response Relationship, Drug, biology, 010405 organic chemistry, Chemistry, QK, Isoniazid, DNA-Directed RNA Polymerases, General Chemistry, biology.organism_classification, Antimicrobial, medicine.disease, QR, Anti-Bacterial Agents, 3. Good health, 0104 chemical sciences, Rifampicin, RC, medicine.drug |
| الوصف: | An antimicrobial activity screen of Burkholderia gladioli BCC0238, a clinical isolate from a cystic fibrosis patient, led to the discovery of gladiolin, a novel macrolide antibiotic with potent activity against Mycobacterium tuberculosis H37Rv. Gladiolin is structurally related to etnangien, a highly unstable antibiotic from Sorangium cellulosum that is also active against Mycobacteria. Like etnangien, gladiolin was found to inhibit RNA polymerase, a validated drug target in M. tuberculosis. However, gladiolin lacks the highly labile hexaene moiety of etnangien and was thus found to possess significantly increased chemical stability. Moreover, gladiolin displayed low mammalian cytotoxicity and good activity against several M. tuberculosis clinical isolates, including four that are resistant to isoniazid and one that is resistant to both isoniazid and rifampicin. Overall, these data suggest that gladiolin may represent a useful starting point for the development of novel drugs to tackle multidrug-resistant tuberculosis. The B. gladioli BCC0238 genome was sequenced using Single Molecule Real Time (SMRT) technology. This resulted in four contiguous sequences: two large circular chromosomes and two smaller putative plasmids. Analysis of the chromosome sequences identified 49 putative specialized metabolite biosynthetic gene clusters. One such gene cluster, located on the smaller of the two chromosomes, encodes a trans-acyltransferase (trans-AT) polyketide synthase (PKS) multienzyme that was hypothesized to assemble gladiolin. Insertional inactivation of a gene in this cluster encoding one of the PKS subunits abrogated gladiolin production, confirming that the gene cluster is responsible for biosynthesis of the antibiotic. Comparison of the PKSs responsible for the assembly of gladiolin and etnangien showed that they possess a remarkably similar architecture, obfuscating the biosynthetic mechanisms responsible for most of the structural differences between the two metabolites. |
| وصف الملف: | application/pdf |
| تدمد: | 1520-5126 0002-7863 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::586b3ab600c87e94f117a85404aa47ac https://doi.org/10.1021/jacs.7b03382 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....586b3ab600c87e94f117a85404aa47ac |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 15205126 00027863 |
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