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  Rational prioritization strategy allows the design of macrolide derivatives that overcome antibiotic resistance

König, G., Sokkar, P., Pryk, N., Heinrich, S., Möller, D., Cimicata, G., et al. (2021). Rational prioritization strategy allows the design of macrolide derivatives that overcome antibiotic resistance. Proceedings of the National Academy of Sciences of the United States of America, 118(46): e2113632118. doi:10.1073/pnas.2113632118.

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 Creators:
König, Gerhard1, Author              
Sokkar, Pandian2, 3, Author              
Pryk, Niclas4, Author
Heinrich, Sascha4, Author
Möller, David4, Author
Cimicata, Giuseppe5, Author
Matzov, Donna5, Author
Dietze, Pascal6, Author
Thiel, Walter1, Author              
Bashan, Anat5, Author
Bandow, Julia Elisabeth6, Author
Zuegg, Johannes7, Author
Yonath, Ada5, Author
Schulz, Frank4, Author
Sanchez-Garcia, Elsa2, 3, Author              
Affiliations:
1Research Department Thiel, Max-Planck-Institut für Kohlenforschung, Max Planck Society, ou_1445590              
2Research Group Sánchez-García, Max-Planck-Institut für Kohlenforschung, Max Planck Society, ou_1950289              
3Department of Computational Biochemistry, University of Duisburg-Essen, 45141 Essen, Germany, ou_persistent22              
4Fakultät für Chemie und Biochemie, Ruhr-Universität Bochum, 44801 Bochum, Germany, ou_persistent22              
5Department of Chemical and Structural Biology, Weizmann Institute, Rehovot 76100 001, Israel, ou_persistent22              
6Fakultät für Biologie und Biotechnologie, Ruhr-Universität Bochum, 44801 Bochum, Germany, ou_persistent22              
7Community for Open Antimicrobial Drug Discovery, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia, ou_persistent22              

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 Abstract: Antibiotic resistance is a major threat to global health; this problem can be addressed by the development of new antibacterial agents to keep pace with the evolutionary adaptation of pathogens. Computational approaches are essential tools to this end since their application enables fast and early strategical decisions in the drug development process. We present a rational design approach, in which acylide antibiotics were screened based on computational predictions of solubility, membrane permeability, and binding affinity toward the ribosome. To assess our design strategy, we tested all candidates for in vitro inhibitory activity and then evaluated them in vivo with several antibiotic-resistant strains to determine minimal inhibitory concentrations. The predicted best candidate is synthetically more accessible, exhibits higher solubility and binding affinity to the ribosome, and is up to 56 times more active against resistant pathogens than telithromycin. Notably, the best compounds designed by us show activity, especially when combined with the membrane-weakening drug colistin, against Acinetobacter baumanii, Pseudomonas aeruginosa, and Escherichia coli, which are the three most critical targets from the priority list of pathogens of the World Health Organization.

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Language(s): eng - English
 Dates: 2021-07-262021-09-242021-11-082021-11-16
 Publication Status: Published in print
 Pages: 7
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1073/pnas.2113632118
 Degree: -

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Title: Proceedings of the National Academy of Sciences of the United States of America
  Other : PNAS
  Other : Proceedings of the National Academy of Sciences of the USA
  Abbreviation : Proc. Natl. Acad. Sci. U. S. A.
Source Genre: Journal
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Publ. Info: Washington, D.C. : National Academy of Sciences
Pages: - Volume / Issue: 118 (46) Sequence Number: e2113632118 Start / End Page: - Identifier: ISSN: 0027-8424
CoNE: https://pure.mpg.de/cone/journals/resource/954925427230