Elucidation of unusual biosynthesis and DnaN-targeting mode of action of potent anti-tuberculosis antibiotics Mycoplanecins

Chengzhang Fu, Yunkun Liu, Christine Walt, Sari Rasheed, Chantal D. Bader, Peer Lukat, Markus Neuber, F. P. Jake Haeckl, Wulf Blankenfeldt, Olga V. Kalinina and Rolf Müller ()
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Chengzhang Fu: Saarland University
Yunkun Liu: Saarland University
Christine Walt: Saarland University
Sari Rasheed: Saarland University
Chantal D. Bader: Saarland University
Peer Lukat: Helmholtz Centre for Infection Research
Markus Neuber: Saarland University
F. P. Jake Haeckl: Saarland University
Wulf Blankenfeldt: Helmholtz Centre for Infection Research
Olga V. Kalinina: Saarland University
Rolf Müller: Saarland University

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-44953-5

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