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Published on: December 6, 2017
Structure-Based Discovery of a New LpxH-Targeted Chemotype with Activity against Klebsiella pneumoniae
Gao Zhang1, C Skyler Cochrane2, Bochao Yang1
1State Key Laboratory of Bioactive Substance and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Abstract:
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.
Insights
Researchers identified a new class of LpxH inhibitors, acetylpiperazines, to combat Gram-negative pathogens. This discovery offers a promising avenue for developing novel antibiotics against challenging bacterial infections.
Area of Science:
- Medicinal Chemistry
- Structural Biology
- Microbiology
Background:
- Gram-negative bacteria possess a protective outer membrane hindering antibiotic efficacy.
- LpxH, a key enzyme in lipid A biosynthesis, is a potential target for antimicrobial drugs.
- The unique binding pocket of LpxH has limited the development of effective inhibitors.
Purpose of the Study:
- To identify novel inhibitors of LpxH by exploring a broader chemical space.
- To validate the efficacy and binding mode of newly discovered LpxH inhibitors.
- To establish a new class of compounds for future antibiotic development.
Main Methods:
- A multistage virtual screening workflow combining pharmacophore modeling, query matching, and docking.
- Synthesis and biochemical evaluation of identified inhibitor compounds.
- X-ray crystallography to determine the binding structure of inhibitors with LpxH.
Main Results:
- Virtual screening identified acetylpiperazine compound F523-0608 as a moderate inhibitor of Klebsiella pneumoniae LpxH (KpLpxH).
- Optimization led to compound 7, a potent LpxH inhibitor (IC50: 0.17 μM) with moderate antibacterial activity (MIC: 5.3 μg/mL).
- Crystal structure analysis confirmed the binding mode of compound 7, validating the virtual screening approach.
Conclusions:
- Acetylpiperazine derivatives represent a novel class of LpxH inhibitors.
- The developed virtual screening strategy is effective for identifying new antimicrobial leads.
- These findings provide a basis for developing new antibiotics against Gram-negative pathogens.
