Author: Krupkin, Miri ; Zimmerman, Ella ; Matzov, Donna ; Yonath, Ada ; Bashan, Anat ; Eyal, Zohar ; Diskin Posner, Yael ; Rozenberg, Haim ; Wekselman, Itai

Significance Resistance to antibiotics poses a serious threat in contemporary medicine. Avilamycin and evernimicin, polysaccharide antibiotics belonging to the orthosomycin family, possess inhibitory activity against multidrug-resistant pathogenic strains of Enterococci , Staphylococci , and other Streptococci gram-positive bacteria by paralyzing ribosomes function in protein biosynthesis. The crystal structures of the large ribosomal subunit from the eubacteria Deinococcus radiodurans in complex with avilamycin and evernimicin revealed their binding sites at the entrance to the A-site tRNA accommodating corridor, thus illuminating the mechanisms of their translation inhibition. Analysis of the binding interactions of these antibiotics depicted the features enabling their species discrimination (namely, selectivity) and elucidated the various mechanisms by which pathogens use single mutations to acquire resistance to those drugs.

05 Jul 2016·Proceedings of the National Academy of SciencesQ1 · CROSS-FIELD

Structures of the orthosomycin antibiotics avilamycin and evernimicin in complex with the bacterial 70S ribosome

Q1 · CROSS-FIELD

Article

Author: Wilson, Daniel N. ; Graf, Michael ; Arenz, Stefan ; Huter, Paul ; Nguyen, Fabian ; Blanchard, Scott C. ; Juette, Manuel F. ; Polikanov, Yury S.

SignificanceThe ribosome is the protein-synthesizing machine of the cell and is a major target for antibiotics. The increase in multidrug-resistant bacteria has limited the utility of our current arsenal of clinically used antibiotics, highlighting the need for further development of compounds that have distinct binding sites and do not display cross-resistance. Using cryo-electron microscopy, we have visualized the binding site of the orthosomycins evernimicin and avilamycin on the bacterial 70S ribosome. The binding site and mode of interaction of evernimicin and avilamycin are distinct from other ribosome-targeting antibiotics. Together with single-molecule studies, our structures reveal how the orthosomycin antibiotics inhibit protein synthesis by preventing accommodation of the aminoacyl-tRNA at the A site of the ribosome.

01 May 2011·Chemistry & Biology

Differential Effects of Thiopeptide and Orthosomycin Antibiotics on Translational GTPases

Article

Author: Barry S. Cooperman ; Daniel N. Wilson ; Agata L. Starosta ; Hanqing Liu ; Yuanwei Chen ; Marina Ivanova ; Viter Márquez ; Aleksandra Mikolajka

The ribosome is a major target in the bacterial cell for antibiotics. Here, we dissect the effects that the thiopeptide antibiotics thiostrepton (ThS) and micrococcin (MiC) as well as the orthosomycin antibiotic evernimicin (Evn) have on translational GTPases. We demonstrate that, like ThS, MiC is a translocation inhibitor, and that the activation by MiC of the ribosome-dependent GTPase activity of EF-G is dependent on the presence of the ribosomal proteins L7/L12 as well as the G' subdomain of EF-G. In contrast, Evn does not inhibit translocation but is a potent inhibitor of back-translocation as well as IF2-dependent 70S-initiation complex formation. Collectively, these results shed insight not only into fundamental aspects of translation but also into the unappreciated specificities of these classes of translational inhibitors.

100 Deals associated with Evernimicin

External Link

KEGG	Wiki	ATC	Drug Bank
D04119	-	-	DB06431

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Bacterial Infections	Phase 3	US	Schering-Plough Corp.	-
Gram-Positive Bacterial Infections	Phase 3	-	Merck Sharp & Dohme Corp.	-

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis