Development of Fragment-Based Inhibitors of the Bacterial Deacetylase LpxC with Low Nanomolar Activity

In a fragment-based approach using NMR spectroscopy, benzyloxyacetohydroxamic acid-derived inhibitors of the bacterial deacetylase LpxC bearing a substituent to target the uridine diphosphate-binding site of the enzyme were developed. By appending privileged fragments via a suitable linker, potent LpxC inhibitors with promising antibacterial activities could be obtained, like the one-digit nanomolar LpxC inhibitor (S)-13j [Ki (EcLpxC C63A) = 9.5 nM; Ki (PaLpxC): 5.6 nM]. To rationalize the observed structure-activity relationships, molecular docking and molecular dynamics studies were performed. Initial in vitro absorption-distribution-metabolism-excretion-toxicity (ADMET) studies of the most potent compounds have paved the way for multiparameter optimization of our newly developed isoserine-based amides.