 |
PDBsum entry 6ccs
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Transferase/antibiotic
|
PDB id
|
|
|
|
6ccs
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
References listed in PDB file
|
|
|
Key reference
|
|
|
Title
|
|
Fragment-Based drug discovery of inhibitors of phosphopantetheine adenylyltransferase from gram-Negative bacteria.
|
|
|
Authors
|
|
R.J.Moreau,
C.K.Skepper,
B.A.Appleton,
A.Blechschmidt,
C.J.Balibar,
B.M.Benton,
J.E.Drumm,
B.Y.Feng,
M.Geng,
C.Li,
M.K.Lindvall,
A.Lingel,
Y.Lu,
M.Mamo,
W.Mergo,
V.Polyakov,
T.M.Smith,
K.Takeoka,
K.Uehara,
L.Wang,
J.R.Wei,
A.H.Weiss,
L.Xie,
W.Xu,
Q.Zhang,
J.De vicente.
|
|
|
Ref.
|
|
J Med Chem, 2018,
61,
3309-3324.
[DOI no: ]
|
|
|
PubMed id
|
|
|
|
|
|
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.
|
|
|
|
|
|
|
