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Antibiotics 2016, 5(4), 32; doi:10.3390/antibiotics5040032

The Novel Aminomethylcycline Omadacycline Has High Specificity for the Primary Tetracycline-Binding Site on the Bacterial Ribosome

1
Microbiology, Department of Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91058 Erlangen, Germany
2
Structural Biology Unit, CIC bioGUNE, 48160 Derio, Bizkaia, Spain
3
IKERBASQUE, Basque Foundation for Science, 48013 Bilbao, Spain
4
Paratek Pharmaceuticals Inc., King of Prussia, PA 19406, USA
5
Institute of Molecular Pathogenesis, Friedrich-Loeffler-Institut, 07743 Jena, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Claudio O. Gualerzi
Received: 27 March 2016 / Revised: 1 September 2016 / Accepted: 12 September 2016 / Published: 22 September 2016
(This article belongs to the Special Issue Inhibitors of the Translational Apparatus)
View Full-Text   |   Download PDF [3905 KB, uploaded 22 September 2016]   |  

Abstract

Omadacycline is an aminomethylcycline antibiotic with potent activity against many Gram-positive and Gram-negative pathogens, including strains carrying the major efflux and ribosome protection resistance determinants. This makes it a promising candidate for therapy of severe infectious diseases. Omadacycline inhibits bacterial protein biosynthesis and competes with tetracycline for binding to the ribosome. Its interactions with the 70S ribosome were, therefore, analyzed in great detail and compared with tigecycline and tetracycline. All three antibiotics are inhibited by mutations in the 16S rRNA that mediate resistance to tetracycline in Brachyspira hyodysenteriae, Helicobacter pylori, Mycoplasma hominis, and Propionibacterium acnes. Chemical probing with dimethyl sulfate and Fenton cleavage with iron(II)-complexes of the tetracycline derivatives revealed that each antibiotic interacts in an idiosyncratic manner with the ribosome. X-ray crystallography had previously revealed one primary binding site for tetracycline on the ribosome and up to five secondary sites. All tetracyclines analyzed here interact with the primary site and tetracycline also with two secondary sites. In addition, each derivative displays a unique set of non-specific interactions with the 16S rRNA. View Full-Text
Keywords: tetracycline; tigecycline; omadacycline; tetracycline resistance; antibiotics; antibiotic resistance; chemical probing; ribosome structure tetracycline; tigecycline; omadacycline; tetracycline resistance; antibiotics; antibiotic resistance; chemical probing; ribosome structure
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MDPI and ACS Style

Heidrich, C.G.; Mitova, S.; Schedlbauer, A.; Connell, S.R.; Fucini, P.; Steenbergen, J.N.; Berens, C. The Novel Aminomethylcycline Omadacycline Has High Specificity for the Primary Tetracycline-Binding Site on the Bacterial Ribosome. Antibiotics 2016, 5, 32.

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