A Study of a Potent Inhibitor against a GDP-6-Deoxy-α-d-Manno-Heptose Biosynthesis Pathway as Antibiotic Candidates
- 주제(키워드) biosynthesis pathway of GDP-6-deoxy-α-d-manno-heptose , electrospray ionization mass spectroscopy , nucleotide-activated heptose , Yersinia pseudotuberculosis , yersiniosis
- 등재 SCIE, SCOPUS
- 발행기관 Mary Ann Liebert Inc.
- 발행년도 2020
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000168916
- 본문언어 영어
- Published As https://dx.doi.org/10.1089/mdr.2019.0144
- PubMed https://pubmed.ncbi.nlm.nih.gov/31613705
- 저작권 이화여자대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
The GDP-6-deoxy-α-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-α-d-manno-heptose is lethal or increases antibiotics susceptibility to pathogens. In this study, we assayed d-glycero-α-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-α-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 α-d-mannose-1-phosphate (αM1P). Chembridge 7929959 shows that the half maximal inhibitory concentration (IC50) is 0.222 μM indicating its affinity with αM1P. © Copyright 2020, Mary Ann Liebert, Inc.
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