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Fragment-Based Drug Discovery of Inhibitors of Phosphopantetheine Adenylyltransferase from Gram-Negative Bacteria

Appleton, Brent and Blechschmidt, Anke and Balibar, Carl and Benton, Bret and De Vicente Fidalgo, Javier and Drumm Iii, Joseph and Feng, Brian and Geng, Mei and Lingel, Andreas and Lu, Yipin and Mamo, Mulugeta and Mergo, Wosenu and Moreau, Bob and Polyakov, Valery and Skepper, Colin and Smith, Thomas and Takeoka, Ken and Uehara, Kyoko and Wang, Lisha and Wei, Jun-Rong and Weiss, Andrew and Xie, Lili and Xu, Wenjian and Zhang, Qiong and Li, Cindy (2018) Fragment-Based Drug Discovery of Inhibitors of Phosphopantetheine Adenylyltransferase from Gram-Negative Bacteria. Journal of Medicinal Chemistry, 61 (8). pp. 3309-3324. ISSN 15204804

Abstract

The discovery and development of new antibiotics capable of curing infections due to multidrug-resistant and pandrug-resistant Gram-negative bacteria are a major challenge with fundamental importance to our global healthcare system. Part of our broad program at Novartis to address this urgent, unmet need includes the search for new agents that inhibit novel bacterial targets. Here we report the discovery and hit-to-lead optimization of new inhibitors of phosphopantetheine adenylyltransferase (PPAT) from Gram-negative bacteria. Utilizing a fragment-based screening approach, we discovered a number of unique scaffolds capable of interacting with the pantetheine site of E. coli PPAT and inhibiting enzymatic activity, including triazolopyrimidinone 6. Structure-based optimization resulted in the identification of two lead compounds as selective, small molecule inhibitors of bacterial PPAT: triazolopyrimidinone 53 and azabenzimidazole 54 efficiently inhibited E. coli and P. aeruginosa PPAT and displayed modest cellular potency against the efflux-deficient E. coli ΔtolC mutant strain.

Item Type: Article
Date Deposited: 26 May 2018 00:45
Last Modified: 25 Jan 2019 00:45
URI: https://oak.novartis.com/id/eprint/32420

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