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Angewandte Chemie - 2023 - El Bakali.pdf (3.6 MB)

Chemical validation of Mycobacterium tuberculosis phosphopantetheine adenylyltransferase using fragment linking and CRISPR interference

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posted on 2023-08-29, 13:27 authored by Jamal El Bakali, Michal Blaszczyk, Joanna C Evans, Jennifer A Boland, William J McCarthy, Imam Fathoni, Marcio VB Dias, Eachan O Johnson, Anthony G Coyne, Valerie Mizrahi, Tom L Blundell, Chris Abell, Christina Spry
The coenzyme A (CoA) biosynthesis pathway has attracted attention as a potential target for much-needed novel antimicrobial drugs, including for the treatment of tuberculosis (TB), the lethal disease caused by Mycobacterium tuberculosis (Mtb). Seeking to identify inhibitors of Mtb phosphopantetheine adenylyltransferase (MtbPPAT), the enzyme that catalyses the penultimate step in CoA biosynthesis, we performed a fragment screen. In doing so, we discovered three series of fragments that occupy distinct regions of the MtbPPAT active site, presenting a unique opportunity for fragment linking. Here we show how, guided by X-ray crystal structures, we could link weakly-binding fragments to produce an active site binder with a KD <20 μM and on-target anti-Mtb activity, as demonstrated using CRISPR interference. This study represents a big step toward validating MtbPPAT as a potential drug target and designing a MtbPPAT-targeting anti-TB drug.

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Crick (Grant ID: CC2169, Grant title: Johnson CC2169)

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