Structure-Based Discovery of a New LpxH-Targeted Chemotype with Activity against Klebsiella pneumoniae.

Gram-negative pathogens are difficult to treat because their outer membrane, enriched with lipid A-anchored lipopolysaccharide, serves as a protective barrier to many antibiotics. LpxH, an essential dimanganese hydrolase in lipid A biosynthesis, represents a promising antimicrobial target, but its distinct L-shaped binding pocket has limited inhibitor development, with only the sulfonylpiperazine chemotype reported to date. To broaden the chemical space, we developed a multistage virtual screening workflow combining HipHop-based pharmacophore modeling, ROCS-based query matching, and FRED docking. This pipeline identified F523-0608, an acetylpiperazine-containing compound, as a moderate Klebsiella pneumoniae LpxH (KpLpxH) inhibitor. Substructure searching and optimization yielded compound 7, a potent inhibitor (IC50: 0.17 μM) with moderate antibacterial activity (MIC: 5.3 μg/mL). The crystal structure of the KpLpxH-compound 7 complex revealed its binding mode, validating virtual screening analysis. These studies establish acetylpiperazine derivatives as a new class of LpxH inhibitors and provide a foundation for future antibiotic development.

Duke Scholars

Author Pei Zhou Biochemistry