Fig. 1: Rationale design of AcpS active site inhibitors.
From: Computer-aided drug design to generate a unique antibiotic family
a AcpS catalyzes the transfer of a 4’-phosphopantetheine moiety from coenzyme A onto a conserved Ser residue of apo-ACP producing 3’5’-adenosine bisphosphate and holo-ACP. b Exemplar compounds from the three generations of thienyltetrazole-focused library. Compounds in Generation 1 (Gen 1) were optimized to find a plateau of AcpS potency and were physiochemically optimized through Generation 2 (Gen 2) for bacterial cell permeability (via MIC) as denoted by the double circle, to arrive at Generation 3 (Gen 3) compounds that can both inhibit AcpS and permeate bacterial membranes. Average values of each property are shown left to right across the library optimization. Several compounds, as the focused library evolved, rose to the potency of low μM inhibitors of AcpS IC50 and low μg/ml MIC against the test organism, MRSA. c Predicted top pose (after minimization) of DNM0547 in the AcpS active site. Proximal cationic and lipophilic residues are prominently labeled: Lys63 A chain; Phe41, Arg46, Phe50, Arg54, Lys87 B chain.
