Chemical validation of Mycobacterium tuberculosis phosphopantetheine adenylyltransferase using fragment linking and CRISPR interference
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Jamal El Bakali Michal Blaszczyk Joanna Evans Jennifer A Boland William McCarthy Imam Fathoni Marcio VB Dias Eachan Johnson Anthony G Coyne Valerie Mizrahi Tom L Blundell Chris Abell Christina SpryAbstract
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.
Journal details
Volume
62
Issue number
17
Pages
e202300221
Available online
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10.1002/anie.202300221
Europe PubMed Central
36757665
Pubmed
36757665
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