Please use this identifier to cite or link to this item: doi:10.22028/D291-41689
Title: Elucidation of unusual biosynthesis and DnaN-targeting mode of action of potent anti-tuberculosis antibiotics Mycoplanecins
Author(s): Fu, Chengzhang
Liu, Yunkun
Walt, Christine
Rasheed, Sari
Bader, Chantal D.
Lukat, Peer
Neuber, Markus
Haeckl, F. P. Jake
Blankenfeldt, Wulf
Kalinina, Olga V.
Müller, Rolf
Language: English
Title: Nature Communications
Volume: 15
Issue: 1
Publisher/Platform: Springer Nature
Year of Publication: 2024
Free key words: Antibiotics
Enzyme mechanisms
Natural product synthesis
Target identification
DDC notations: 500 Science
Publikation type: Journal Article
Abstract: DNA polymerase III sliding clamp (DnaN) was recently validated as a new antituberculosis 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.
DOI of the first publication: 10.1038/s41467-024-44953-5
URL of the first publication:
Link to this record: urn:nbn:de:bsz:291--ds-416890
ISSN: 2041-1723
Date of registration: 1-Mar-2024
Description of the related object: Supplementary information
Related object:
Faculty: M - Medizinische Fakultät
NT - Naturwissenschaftlich- Technische Fakultät
Department: M - Medizinische Biometrie, Epidemiologie und medizinische Informatik
NT - Pharmazie
Professorship: M - Prof. Dr. Olga Kalinina
NT - Prof. Dr. Rolf Müller
Collections:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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