Identification of selective inhibitors of Helicobacter pylori IMPDH as a targeted therapy for the infection

Helicobacter pylori ( H. pylori ), the major cause of several gastric disorders has been recognied as a type I carcinogen. By virtue of resistance developed by H. pylori strains, currently used antibiotic based treatments rather demonstrate high failure rates. Hence, there is an emerging need for id...

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Bibliographic Details
Published in:Scientific reports 2019-01, Vol.9 (1), p.190, Article 190
Main Authors: Juvale, Kapil, Purushothaman, Gayathri, Singh, Vijay, Shaik, Althaf, Ravi, Srimadhavi, Thiruvenkatam, Vijay, Kirubakaran, Sivapriya
Format: Article
Language:English
Subjects:
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639/638
82/80
82/83
Anti-Bacterial Agents - pharmacology
Anti-Bacterial Agents - therapeutic use
Bacterial Proteins
Benzimidazoles
Dehydrogenase
Dehydrogenases
Enzyme Inhibitors
Enzyme kinetics
Helicobacter Infections - drug therapy
Helicobacter pylori
Helicobacter pylori - enzymology
Humanities and Social Sciences
Humans
IMP Dehydrogenase - antagonists & inhibitors
Indoles
Indoles - chemistry
Indoles - pharmacology
Infections
Inhibitors
Inosine monophosphate
Kinetics
Molecular Targeted Therapy - methods
multidisciplinary
NAD
Recombinant Proteins
Science
Science (multidisciplinary)
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Summary:Helicobacter pylori ( H. pylori ), the major cause of several gastric disorders has been recognied as a type I carcinogen. By virtue of resistance developed by H. pylori strains, currently used antibiotic based treatments rather demonstrate high failure rates. Hence, there is an emerging need for identification of new targets to treat H. pylori infection. Inosine-5′-monophosphate dehydrogenase (IMPDH) has been studied as a potential target to treat H. pylori infection. Here, a detailed enzyme kinetic study of recombinant expressed H. pylori inosine-5′-monophosphate dehydrogenase ( Hp IMPDH) is presented. A new in-house synthesized indole-based scaffold is identified as an inhibitor for Hp IMPDH. These indole-based compounds showed non-competitive inhibition against IMP and NAD + whereas the benzimidazole compounds were found be uncompetitive inhibitors. The new indole scaffold ensures specificity due to its high selectivity for bacterial IMPDH over human IMPDH II. Our work aims to overcome the drawback of existing inhibitors by introducing new indole scaffold for targeting bacterial IMPDH.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-018-37490-x