Biosynthetic Interrogation of Soil Metagenomes Reveals Metamarin, an Uncommon Cyclomarin Congener with Activity against Mycobacterium tuberculosis
| Autor: | Lei Li, Riccardo Russo, Bimal Koirala, Thahmina Ali, Yozen Hernandez, Logan W MacIntyre, Sean F. Brady |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Tuberculosis
medicine.drug_class medicine.medical_treatment Antibiotics Antitubercular Agents Pharmaceutical Science Microbial Sensitivity Tests Protein degradation 01 natural sciences Article Analytical Chemistry Microbiology Cell Line Mycobacterium tuberculosis Mice Antibiotic resistance Bacterial Proteins Nonribosomal peptide Drug Discovery medicine Animals Gene Heat-Shock Proteins Soil Microbiology Pharmacology chemistry.chemical_classification Protease biology Molecular Structure 010405 organic chemistry Macrophages Organic Chemistry respiratory system biology.organism_classification medicine.disease 0104 chemical sciences 010404 medicinal & biomolecular chemistry Complementary and alternative medicine chemistry Molecular Medicine Metagenome Oligopeptides |
| Zdroj: | Journal of Natural Products |
| ISSN: | 1520-6025 0163-3864 |
| Popis: | Tuberculosis (TB) remains one of the deadliest infectious diseases. Unfortunately, the development of antibiotic resistance threatens our current therapeutic arsenal, which has necessitated the discovery and development of novel antibiotics against drug-resistant Mycobacterium tuberculosis (Mtb). Cyclomarin A and rufomycin I are structurally related cyclic heptapeptides assembled by nonribosomal peptide synthetases (NRPSs), which show potent anti-Mtb activity with a new cellular target, the caseinolytic protein ClpC1. An NRPS adenylation domain survey using DNA extracted from ∼2000 ecologically diverse soils found low cyclomarin/rufomycin biosynthetic diversity. In this survey, a family of cyclomarin/rufomycin-like biosynthetic gene clusters (BGC) that encode metamarin, an uncommon cyclomarin congener with potent activity against both Mtb H37Rv and multidrug-resistant Mtb clinical isolates was identified. Metamarin effectively inhibits Mtb growth in murine macrophages and increases the activities of ClpC1 ATPase and the associated ClpC1/P1/P2 protease complex, thus causing cell death by uncontrolled protein degradation. |
| Databáze: | OpenAIRE |
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