Insights into the Target Interaction of Naturally Occurring Muraymycin Nucleoside Antibiotics

Stefan Koppermann; Zheng Cui; Patrick D. Fischer; Xiachang Wang; Jannine Ludwig; Jon S. Thorson; Steven G. Van Lanen; Christian Ducho

doi:10.1002/cmdc.201700793

Insights into the Target Interaction of Naturally Occurring Muraymycin Nucleoside Antibiotics

Stefan Koppermann, Zheng Cui, Patrick D. Fischer, Xiachang Wang, Jannine Ludwig, Jon S. Thorson, Steven G. Van Lanen, Christian Ducho

Research output: Contribution to journal › Article › peer-review

23 Scopus citations

Abstract

Muraymycins are a subclass of antimicrobially active uridine-derived natural products. Biological data on several muraymycin analogues have been reported, including some inhibitory in vitro activities toward their target protein, the bacterial membrane enzyme MraY. However, a structure–activity relationship (SAR) study on naturally occurring muraymycins based on such in vitro data has been missing so far. In this work, we report a detailed SAR investigation on representatives of the four muraymycin subgroups A–D using a fluorescence-based in vitro MraY assay. For some muraymycins, inhibition of MraY with IC ₅₀ values in the low-picomolar range was observed. These inhibitory potencies were compared with antibacterial activities and were correlated to modelling data derived from a previously reported X-ray crystal structure of MraY in complex with a muraymycin inhibitor. Overall, these results will pave the way for the development of muraymycin analogues with optimized properties as antibacterial drug candidates.

Original language	English
Pages (from-to)	779-784
Number of pages	6
Journal	ChemMedChem
Volume	13
Issue number	8
DOIs	https://doi.org/10.1002/cmdc.201700793
State	Published - Apr 23 2018

Bibliographical note

Funding Information:
We thank the Deutsche Forschungsgemeinschaft (DFG, grant DU 1095/5-1, C.D.), the University of Kentucky College of Pharmacy, the University of Kentucky Markey Cancer Center, the National Center for Advancing Translational Sciences (UL1TR001998, X.W., J.S.T.) and the National Institutes of Health (NIH, grant AI087849, Z.C., S.G.V.L.) for financial support. P.D.F. is grateful for a doctoral fellowship of the Fonds der Chemischen Industrie (FCI). We also thank Professor Seok-Yong Lee (Duke University Medical Center) for providing us with the plasmid for the overexpression of MraY from A. aeolicus.

Publisher Copyright:
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Keywords

activity assays
antibiotics
natural products
nucleosides
structure–activity relationships

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Pharmacology
Drug Discovery
Pharmacology, Toxicology and Pharmaceutics (all)
Organic Chemistry

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10.1002/cmdc.201700793

Cite this

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title = "Insights into the Target Interaction of Naturally Occurring Muraymycin Nucleoside Antibiotics",

abstract = " Muraymycins are a subclass of antimicrobially active uridine-derived natural products. Biological data on several muraymycin analogues have been reported, including some inhibitory in vitro activities toward their target protein, the bacterial membrane enzyme MraY. However, a structure–activity relationship (SAR) study on naturally occurring muraymycins based on such in vitro data has been missing so far. In this work, we report a detailed SAR investigation on representatives of the four muraymycin subgroups A–D using a fluorescence-based in vitro MraY assay. For some muraymycins, inhibition of MraY with IC 50 values in the low-picomolar range was observed. These inhibitory potencies were compared with antibacterial activities and were correlated to modelling data derived from a previously reported X-ray crystal structure of MraY in complex with a muraymycin inhibitor. Overall, these results will pave the way for the development of muraymycin analogues with optimized properties as antibacterial drug candidates.",

keywords = "activity assays, antibiotics, natural products, nucleosides, structure–activity relationships",

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note = "Funding Information: We thank the Deutsche Forschungsgemeinschaft (DFG, grant DU 1095/5-1, C.D.), the University of Kentucky College of Pharmacy, the University of Kentucky Markey Cancer Center, the National Center for Advancing Translational Sciences (UL1TR001998, X.W., J.S.T.) and the National Institutes of Health (NIH, grant AI087849, Z.C., S.G.V.L.) for financial support. P.D.F. is grateful for a doctoral fellowship of the Fonds der Chemischen Industrie (FCI). We also thank Professor Seok-Yong Lee (Duke University Medical Center) for providing us with the plasmid for the overexpression of MraY from A. aeolicus. Publisher Copyright: {\textcopyright} 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim",

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AU - Van Lanen, Steven G.

AU - Ducho, Christian

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N2 - Muraymycins are a subclass of antimicrobially active uridine-derived natural products. Biological data on several muraymycin analogues have been reported, including some inhibitory in vitro activities toward their target protein, the bacterial membrane enzyme MraY. However, a structure–activity relationship (SAR) study on naturally occurring muraymycins based on such in vitro data has been missing so far. In this work, we report a detailed SAR investigation on representatives of the four muraymycin subgroups A–D using a fluorescence-based in vitro MraY assay. For some muraymycins, inhibition of MraY with IC 50 values in the low-picomolar range was observed. These inhibitory potencies were compared with antibacterial activities and were correlated to modelling data derived from a previously reported X-ray crystal structure of MraY in complex with a muraymycin inhibitor. Overall, these results will pave the way for the development of muraymycin analogues with optimized properties as antibacterial drug candidates.

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Insights into the Target Interaction of Naturally Occurring Muraymycin Nucleoside Antibiotics

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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