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Journal article
Rational prioritization strategy allows the design of macrolide derivatives that overcome antibiotic resistance
Proceedings of the National Academy of Sciences - PNAS, Vol.118(46), e2113632118
08/Nov/2021
PMID: 34750269
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.
Details
- Title
- Rational prioritization strategy allows the design of macrolide derivatives that overcome antibiotic resistance
- Creators
- Gerhard König - University of PortsmouthPandian Sokkar - Department of Computational Biochemistry, University of Duisburg-Essen, 45141 Essen, GermanyNiclas Pryk - Ruhr University BochumSascha Heinrich - Ruhr University BochumDavid Möller - Ruhr University BochumGiuseppe Cimicata - 972WIS_INST___9Donna Matzov - 972WIS_INST___9Pascal Dietze - Ruhr University BochumWalter Thiel - Ruhr University BochumAnat Bashan - 972WIS_INST___9Julia Elisabeth Bandow - Ruhr University BochumJohannes Zuegg - Community for Open Antimicrobial Drug Discovery, Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, AustraliaAda Yonath (Corresponding Author) - 972WIS_INST___9Frank Schulz (Corresponding Author) - Ruhr University BochumElsa Sanchez-Garcia (Corresponding Author) - Department of Computational Biochemistry, University of Duisburg-Essen, 45141 Essen, Germany
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.118(46), e2113632118; 08/Nov/2021
- Number of pages
- 7
- Language
- English
- DOI
- https://doi.org/10.1073/pnas.2113632118
- PMID
- 34750269
- Grant note
- This work was supported by the German Research Foundation (DFG) under Germany’s Excellence Strategy EXC 2033–390677874–RESOLV. P.S. and E.S.-G. acknowledge the Gauss Centre for Supercomputing e.V. (GCS; https://www.gauss-centre.eu) for funding this project by providing computing time on the GCS Supercomputer JUQUEEN at Jülich Supercomputing Centre. J.E.B. acknowledges funding from the Federal State of North Rhine-Westphalia and the European Regional Development Fund for the Research Infrastructure “Center for System-based Antibiotic Research.” A.Y. was supported by European Research Council Grant 322581 “Novel Insights into Multi-Drug Resistance to Antibiotics and the Primordial Ribosome” and the Kimmelman Center for Macromolecular Assemblies; additionally, A.Y. holds the Martin S. and Helen Kimmel Professorial Chair at the Weizmann Institute of Science. F.S. was funded by DFG Research Training Group GRK 2341 “Microbial Substrate Conversion.” E.S.-G. acknowledges the support of the Boehringer Ingelheim Foundation (Plus-3 Program) and of the Collaborative Research Center 1093 “Supramolecular Chemistry on Proteins” funded by the DFG. Author contributions: G.K., F.S., and E.S.-G. designed research; G.K., P.S., N.P., D. Möller, G.C., D. Matzov, P.D., and A.B. performed research; W.T., A.B., J.E.B., J.Z., and A.Y. contributed new reagents/analytic tools; G.K., P.S., N.P., S.H., A.B., A.Y., F.S., and E.S.-G. analyzed data; and G.K., P.S., F.S., and E.S.-G. wrote the paper. G.K., P.S., and N.P. contributed equally to this work.
- Record Identifier
- 993329974603596
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