Abstract
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 (HpIMPDH) is presented. A new in-house synthesized indole-based scaffold is identified as an inhibitor for HpIMPDH. 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.
Highlights
Worldwide more than 50% population is infected by Helicobacter pylori (H. pylori), a gram-negative bacterium which resides in the antral region of stomach[1]
The characterisation of recombinant H. pylori inosine-5′-monophosphate dehydrogenase (HpIMPDH) by LC-MS/MS resulted in 65% sequence match using peptide mass fingerprint analysis between recombinant HpIMPDH and the HpIMPDH protein sequence obtained from the database
Bacterial Inosine-5′-monophosphate dehydrogenase (IMPDH), a vital enzyme in the nucleotide biosynthesis pathway has recently received a lot of attention as a possible target to treat multi-drug resistant infections
Summary
Expression, Purification and Characterization of HpIMPDH. The recombinant HpIMPDH. The uncompetitive behaviour of 1 towards both IMP and NAD+ suggests that it has a strong preference for binding to the E-XMP* complex[15] This will be highly advantageous in-vivo as increased substrate concentration would lead to increased inhibition of the IMPDH unlike competitive behavior. The residues, 280–340 (Fig. 7), form a part of the flap region of the active site binds to NAD+ This region is highly divergent in HsIMPDH-II and Pro-IMPDHs which make this region a suitable target to design species-specific inhibitors[6,15,29,30]. These strong interactions of 2 at the active site can be reasoned for its activity towards HpIMPDH (Fig. 8)
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