Membrane-interacting properties of the functionalised fatty acid moiety of muraymycin antibiotics

Ries, Oliver; Carnarius, Christian; Steinem, Claudia; Ducho, Christian

doi:10.1039/c4md00526k

Cited by 14 publications

(13 citation statements)

References 41 publications

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“…We have reported a model system to study the membrane-interacting properties of the ω-functionalized fatty acid moiety of A-series muraymycins such as 3 , indicating both an efficient membrane accumulation and penetration mediated by the guanidinium-containing structural motif. [13] This present study encourages further investigations on the membrane-penetrating properties of O -acylated muraymycins of the A- and B-groups.…”

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confidence: 62%

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Insights into the Target Interaction of Naturally Occurring Muraymycin Nucleoside Antibiotics

et al. 2018

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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 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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confidence: 62%

“…This finding supports a previous hypothesis that the fatty acyl unit might instead contribute primarily to the cellular uptake rather than target interaction. [10d,13] On the other hand, muraymycin D1 7 was a ca. 30-fold less active MraY inhibitor than C1 6 , although it only differs in the missing β-hydroxy group in the leucine moiety.…”

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Insights into the Target Interaction of Naturally Occurring Muraymycin Nucleoside Antibiotics

et al. 2018

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“…Ries et al have further shown that the -guanylated fatty acid substituent found in the most active muraymycins is important for localisation of the antibiotic into the cytoplasmic membrane of the target organism [26].…”

Section: Nucleoside Natural Product Inhibitors Of Mray and Related Enmentioning

confidence: 99%

Inhibition of phospho-MurNAc-pentapeptide translocase (MraY) by nucleoside natural product antibiotics, bacteriophage ϕX174 lysis protein E, and cationic antibacterial peptides

Bugg

Rodolis

Mihalyi

et al. 2016

Bioorganic & Medicinal Chemistry

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“…Consequently, the need emerged to find suitable methods to evaluate and predict the permeability of antiinfectives. These attempts include in vitro approaches such as liposome [14] or outermembrane-vesicle swelling assays [15], electrophysiological studies [16][17][18], as well as assays employing lipid-coated filters [19,20], reconstituted bacterial vesicles [21] or giant unilamellar vesicles (GUV's) [22]. Further, important assays have been developed using living bacteria [23][24][25][26].…”

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confidence: 99%

A Hydrogel-Based in Vitro Assay for the Fast Prediction of Antibiotic Accumulation in Gram-Negative Bacteria

Richter¹,

Kamal²,

García-Rivera³

et al. 2020

Preprint

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The pipeline of antibiotics has been for decades on an alarmingly low level. Considering the steadily emerging antibiotic resistance, novel tools are needed for early and easy identification of effective anti-infective compounds. In Gram-negative bacteria, the uptake of anti-infectives is especially limited. We here present a surprisingly simple in vitro model of the Gram-negative bacterial envelope, based on 20% (w/v) potato starch gel, printed on polycarbonate 96-well filter membranes. Rapid permeability measurements across this polysaccharide hydrogel allowed to correctly predict either high or low accumulation for all 16 tested anti-infectives in living E. coli. Freeze-fracture TEM supports that the macromolecular network structure of the starch hydrogel may represent a useful surrogate of the Gram-negative bacterial envelope. Machine learning by random forest analysis of in vitro data revealed minimum projection area, molecular mass, and rigidity as the most critical physicochemical parameters for hydrogel permeability, in agreement with reported structural features needed for uptake into Gram-negative bacteria. Correlating our data set of 27 antibiotics from different structural classes to reported MIC values of seven clinically relevant pathogens allowed to distinguish active from non-active compounds based on their low in vitro permeability and in particular to identify poorly permeable antimicrobial candidates before testing them on living bacteria.<br>

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Membrane-interacting properties of the functionalised fatty acid moiety of muraymycin antibiotics

Abstract: A simplified model system is introduced to elucidate the significance of the ω-functionalised fatty acid moiety of muraymycin nucleoside antibiotics for membrane interaction and penetration.

Cited by 14 publications

References 41 publications

Insights into the Target Interaction of Naturally Occurring Muraymycin Nucleoside Antibiotics

Insights into the Target Interaction of Naturally Occurring Muraymycin Nucleoside Antibiotics

Inhibition of phospho-MurNAc-pentapeptide translocase (MraY) by nucleoside natural product antibiotics, bacteriophage ϕX174 lysis protein E, and cationic antibacterial peptides

A Hydrogel-Based in Vitro Assay for the Fast Prediction of Antibiotic Accumulation in Gram-Negative Bacteria

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