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Inhibiting Heptosyltransferase to Combat Gram‐Negative Bacterial Infections
Author(s) -
Wang Alvin,
Castro Colleen,
Taylor Erika
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.03436
Subject(s) - chemistry , lipid a , antibiotics , enzyme , bacteria , docking (animal) , lipid ii , bacterial outer membrane , biochemistry , antimicrobial , gram negative bacteria , microbiology and biotechnology , combinatorial chemistry , stereochemistry , biosynthesis , biology , gene , escherichia coli , medicine , organic chemistry , genetics , nursing
Lipopolysaccharides (LPS) embedded in the outer membrane of Gram‐negative bacteria are known to enable antibiotic resistance by providing protection from hydrophobic antibiotics and assisting biofilm development. One of the key enzymes for synthesizing LPS is heptosyltransferase I (HepI), which catalyzes the reaction of ADP‐L‐ glycero ‐D‐ manno ‐heptose (ADP‐heptose) with Kdo 2 ‐lipid A, a precursor of LPS. Previous studies have shown that HepI deficiency in bacteria results in increased susceptibility to antibiotics and host immune response. Here, we use molecular docking analysis to obtain binding affinity calculations of 419 natural product ligands provided by the National Cancer Institute (NCI) with HepI as the receptor. Docking calculations were performed with AutoDock Vina with 200 simulations per ligand. 118 ligands were found to have an average binding affinity calculation higher than that of ADP‐heptose. Selected ligands are being investigated for in vitro inhibition of HepI through kinetic analyses using a coupled assay system where ADP, a product of the heptose transfer reaction, is detected using NADH enzyme‐linked photometric assay. Potent HepI inhibitors will be further investigated as novel candidates for antimicrobial development. Support or Funding Information This project is supported by from Wesleyan University and the National Institutes of Health (1R15AI119907‐01).