Discovery and Optimization of Phosphopantetheine Adenylyltransferase Inhibitors with Gram-Negative Antibacterial Activity

In the preceding
manuscript [Moreau et al. 2018, 10.1021/acs.jmedchem.7b01691]
we described a successful fragment-based lead discovery
(FBLD) strategy for discovery of bacterial phosphopantetheine adenylyltransferase
inhibitors (PPAT, CoaD). Following several rounds of optimization
two promising lead compounds were identified: triazolopyrimidinone 3 and 4-azabenzimidazole 4. Here we disclose
our efforts to further optimize these two leads for on-target potency
and Gram-negative cellular activity. Enabled by a robust X-ray crystallography
system, our structure-based inhibitor design approach delivered compounds
with biochemical potencies 4–5 orders of magnitude greater
than their respective fragment starting points. Additional optimization
was guided by observations on bacterial permeability and physicochemical
properties, which ultimately led to the identification of PPAT inhibitors
with cellular activity against wild-type E. coli.