6CCK

Crystal structure of E.coli Phosphopantetheine Adenylyltransferase (PPAT/CoaD) in complex with (R)-3-(3-chlorophenyl)-3-((5-methyl-7-oxo-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)amino)propanenitrile

Summary for 6CCK

• Entry DOI: 10.2210/pdb6cck/pdb
• Descriptor: Phosphopantetheine adenylyltransferase, (3R)-3-(3-chlorophenyl)-3-[(5-methyl-7-oxo-6,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)amino]propanenitrile, ADENOSINE-5'-TRIPHOSPHATE, ... (6 entities in total)
• Functional Keywords: ppat coad fbdd phosphopantetheine adenylyltransferase gram-negative antibacterial antibiotic, transferase, transferase-antibiotic complex, transferase/antibiotic
• Biological source: Escherichia coli (strain K12)
• Cellular location: Cytoplasm : P0A6I6
• Total number of polymer chains: 2
• Total formula weight: 38060.30

Authors

Mamo, M.,Appleton, B.A. (deposition date: 2018-02-07, release date: 2018-03-14, Last modification date: 2024-03-13)

Primary citation

Moreau, R.J.,Skepper, C.K.,Appleton, B.A.,Blechschmidt, A.,Balibar, C.J.,Benton, B.M.,Drumm, J.E.,Feng, B.Y.,Geng, M.,Li, C.,Lindvall, M.K.,Lingel, A.,Lu, Y.,Mamo, M.,Mergo, W.,Polyakov, V.,Smith, T.M.,Takeoka, K.,Uehara, K.,Wang, L.,Wei, J.R.,Weiss, A.H.,Xie, L.,Xu, W.,Zhang, Q.,de Vicente, J.
Fragment-Based Drug Discovery of Inhibitors of Phosphopantetheine Adenylyltransferase from Gram-Negative Bacteria.
J. Med. Chem., 61:3309-3324, 2018

PubMed 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 Δ tolC mutant strain.

PubMed: 29498517
DOI: 10.1021/acs.jmedchem.7b01691

Experimental method

X-RAY DIFFRACTION (1.61 Å)