ArticleNature communications2024
Elucidation of unusual biosynthesis and DnaN-targeting mode of action of potent anti-tuberculosis antibiotics Mycoplanecins.
Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 14 citations in OpenAlex.
- Active-site recognition enables hydroxylation of a fluorine-deactivated C-H bond in 6,6,6-trifluoro-L-norleucine.Chemical communications (Cambridge, England) · 2026Article
- Structure Elucidation, Biosynthesis and Biological Evaluation of Neosorangicin A, a Member of the Sorangicin Family.Journal of natural products · 2026Article
- Systematic Determination of the Impact of Structural Edits on Peptide Accumulation into Mycobacteria.ACS chemical biology · 2025Article
- Total Synthesis of Mycoplanecin A.Organic letters · 2025Article
- Saarvienin A-A Novel Glycopeptide with Potent Activity against Drug-Resistant Bacteria.Angewandte Chemie (International ed. in English) · 2025Article
- Discovery, Herbicidal Activity and Biosynthesis of a Novel Natural Tetramic Acid from Alternaria Species.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Exquisite selectivity of griselimycin extends to beta subunit of DNA polymerases from Gram-negative bacterial pathogens.Communications biology · 2024Article
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
DNA polymerase III sliding clamp (DnaN) was recently validated as a new anti-tuberculosis target employing griselimycins. Three (2 S,4 R)-4-methylproline moieties of methylgriselimycin play significant roles in target binding and metabolic stability. Here, we identify the mycoplanecin biosynthetic gene cluster by genome mining using bait genes from the 4-methylproline pathway. We isolate and structurally elucidate four mycoplanecins comprising scarce homo-amino acids and 4-alkylprolines. Evaluating mycoplanecin E against Mycobacterium tuberculosis surprisingly reveals an excitingly low minimum inhibition concentration at 83 ng/mL, thus outcompeting griselimycin by approximately 24-fold. We show that mycoplanecins bind DnaN with nanomolar affinity and provide a co-crystal structure of mycoplanecin A-bound DnaN. Additionally, we reconstitute the biosyntheses of the unusual L-homoleucine, L-homonorleucine, and (2 S,4 R)-4-ethylproline building blocks by characterizing in vitro the full set of eight enzymes involved. The biosynthetic study, bioactivity evaluation, and drug target validation of mycoplanecins pave the way for their further development to tackle multidrug-resistant mycobacterial infections.
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Registered trials
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