9RFW

Manikomycin bound to the Escherichia coli 50S ribosomal subunit

Summary for 9RFW

• Entry DOI: 10.2210/pdb9rfw/pdb
• EMDB information: 53943
• Related PRD ID: PRD_002603
• Descriptor: Large ribosomal subunit protein bL36A, Large ribosomal subunit protein bL34, Large ribosomal subunit protein bL35, ... (38 entities in total)
• Functional Keywords: dal2, pramp, ribosome, translation, initiation, nascent polypeptide exit tunnel, cryo-em, antibiotic
• Biological source: Escherichia coli BW25113; More
• Total number of polymer chains: 35
• Total formula weight: 1407543.82

Authors

Kaur, M.,Travin, D.,Berger, M.J.,Jangra, M.,Morici, M.,Safdari, H.A.,Guitor, A.K.,Koteva, K.,Xu, M.,Chen, X.,Vazquez-Laslop, N.,Mankin, A.S.,Wilson, D.N.,Wright, G. (deposition date: 2025-06-05, release date: 2026-05-27)

Primary citation

Wright, G.,Kaur, M.,Travin, D.,Berger, M.,Jangra, M.,Morici, M.,Safdari, H.A.,Klepacki, D.,Wang, W.,Cook, M.,Chou, S.,Guitor, A.,Koteva, K.,Xu, M.,Ejim, L.,Macneil, L.,Vazquez-Laslop, N.,Mankin, A.,Wilson, D.
A Natural Depsipeptide Antibiotic that Targets the E site of the Bacterial Ribosome.
Res Sq, 2025

PubMed Abstract: A significant challenge in addressing the antibiotic resistance crisis is identifying new antimicrobial compounds. Although natural products produced by fungi and bacteria, particularly actinomycetes, have been the source of most antibiotics discovered over the past 80 years, they have fallen out of favor due to the frequent rediscovery of known drug scaffolds. The current perception is that antibiotic-producing actinomycetes have been over-mined and possess little novelty left to yield. Here, we demonstrate that by using improved fractionation approaches that enrich previously overlooked minor products, even well-studied strains of antibiotic-producing actinomycetes can provide new chemical scaffolds with unique modes of action. By fractionating a library of natural product extracts from soil bacteria, we show that Streptomyces rimosus, the source of the well-known antibiotic oxytetracycline, produces a previously overlooked cyclic depsipeptide antibiotic that we called manikomycin. Manikomycin can kill multi-drug-resistant Enterobacteriaceae and is not susceptible to resistance associated with clinically used antibiotics. Biochemical, genetic, and structural analyses reveal that manikomycin binds in the 'exit' or E site of the large subunit of the bacterial ribosome preventing the entry of the 3' end of the tRNA into the E site and effectively hindering the translocation step of protein synthesis in a sequence context-specific manner. Manikomycin is the first antibacterial agent to target the critical but underexplored E site in the large ribosomal subunit, highlighting its value as a lead for developing new antibiotics.

PubMed: 40630547
DOI: 10.21203/rs.3.rs-6925047/v1

Experimental method

ELECTRON MICROSCOPY (2.4 Å)