TY - JOUR
T1 - A Study of a Potent Inhibitor against a GDP-6-Deoxy-α-d-Manno-Heptose Biosynthesis Pathway as Antibiotic Candidates
AU - Kim, Suwon
AU - Jo, Seri
AU - Kim, Mi Sun
AU - Shin, Dong Hae
N1 - Funding Information:
This research was supported by the Basic Science Research Programs, 2018R1D1A1B07050781 to D.H.S. and 2018R1D1A1B07050942 to M.-S.K., funded by the National Research Foundation of Korea granted by the Ministry of Education, Science, and Technology (MEST), Republic of Korea.
Publisher Copyright:
© Copyright 2020, Mary Ann Liebert, Inc.
PY - 2020/4
Y1 - 2020/4
N2 - 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.
AB - 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.
KW - Yersinia pseudotuberculosis
KW - biosynthesis pathway of GDP-6-deoxy-α-d-manno-heptose
KW - electrospray ionization mass spectroscopy
KW - nucleotide-activated heptose
KW - yersiniosis
UR - http://www.scopus.com/inward/record.url?scp=85083545633&partnerID=8YFLogxK
U2 - 10.1089/mdr.2019.0144
DO - 10.1089/mdr.2019.0144
M3 - Article
C2 - 31613705
AN - SCOPUS:85083545633
VL - 26
SP - 385
EP - 390
JO - Microbial Drug Resistance
JF - Microbial Drug Resistance
SN - 1076-6294
IS - 4
ER -