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A Study of a Potent Inhibitor Against a GDP-6-Deoxy-alpha-d-Manno-Heptose Biosynthesis Pathway as Antibiotic Candidates

Title
A Study of a Potent Inhibitor Against a GDP-6-Deoxy-alpha-d-Manno-Heptose Biosynthesis Pathway as Antibiotic Candidates
Authors
Kim, SuwonJo, SeriKim, Mi-SunShin, Dong Hae
Ewha Authors
신동해김수원김미선
SCOPUS Author ID
신동해scopus; 김수원scopus
Issue Date
2020
Journal Title
MICROBIAL DRUG RESISTANCE
ISSN
1076-6294JCR Link

1931-8448JCR Link
Citation
MICROBIAL DRUG RESISTANCE vol. 26, no. 4, pp. 385 - 390
Keywords
biosynthesis pathway of GDP-6-deoxy-alpha-d-manno-heptosenucleotide-activated heptoseYersinia pseudotuberculosisyersiniosiselectrospray ionization mass spectroscopy
Publisher
MARY ANN LIEBERT, INC
Indexed
SCIE; SCOPUS WOS scopus
Document Type
Article
Abstract
The GDP-6-deoxy-alpha-d-manno-heptose is a key building block molecule in constructing lipopolysaccharide of Gram-negative bacteria. Therefore, blockage of the biosynthesis pathway of GDP-6-deoxy-alpha-d-manno-heptose is lethal or increases antibiotics susceptibility to pathogens. In this study, we assayed d-glycero-alpha-d-manno-heptose-1-phosphate guanylyltransferase (HddC) from Yersinia pseudotuberculosis (Yp) using an efficient assay method supplying its natural substrate. Using the method, 102 chemical compounds were tested to search inhibitory compounds and electrospray ionization mass spectrometry was used to detect the HddC from Y. pseudotuberculosis (YpHddC) reaction product, GDP-d-glycero-alpha-d-manno-heptose. Interestingly, one promising lead, ethyl 5-({[(5-benzyl-1, 3, 4-oxadiazol-2-yl) thio] acetyl} amino)-4-cyano-3-methyl-2-thiophenecarboxylate (Chembridge 7929959), was discovered. The inhibitory activity of the lead compound against YpHddC has been proven by blocking its nucleotidyltransferase activity transferring the GMP moiety to alpha-d-mannose-1-phosphate (alpha M1P). Chembridge 7929959 shows that the half maximal inhibitory concentration (IC50) is 0.222 mu M indicating its affinity with alpha M1P.
DOI
10.1089/mdr.2019.0144
Appears in Collections:
약학대학 > 약학과 > Journal papers
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