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Species-specific and inhibitor-dependent conformations of LpxC: implications for antibiotic design.

Publication ,  Journal Article
Lee, C-J; Liang, X; Chen, X; Zeng, D; Joo, SH; Chung, HS; Barb, AW; Swanson, SM; Nicholas, RA; Li, Y; Toone, EJ; Raetz, CRH; Zhou, P
Published in: Chem Biol
January 28, 2011

LpxC is an essential enzyme in the lipid A biosynthetic pathway in gram-negative bacteria. Several promising antimicrobial lead compounds targeting LpxC have been reported, though they typically display a large variation in potency against different gram-negative pathogens. We report that inhibitors with a diacetylene scaffold effectively overcome the resistance caused by sequence variation in the LpxC substrate-binding passage. Compound binding is captured in complex with representative LpxC orthologs, and structural analysis reveals large conformational differences that mostly reflect inherent molecular features of distinct LpxC orthologs, whereas ligand-induced structural adaptations occur at a smaller scale. These observations highlight the need for a molecular understanding of inherent structural features and conformational plasticity of LpxC enzymes for optimizing LpxC inhibitors as broad-spectrum antibiotics against gram-negative infections.

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Published In

Chem Biol

DOI

EISSN

1879-1301

Publication Date

January 28, 2011

Volume

18

Issue

1

Start / End Page

38 / 47

Location

United States

Related Subject Headings

  • Species Specificity
  • Sequence Homology, Amino Acid
  • Organic Chemistry
  • Models, Molecular
  • Ligands
  • Enzyme Inhibitors
  • Drug Design
  • Catalytic Domain
  • Bacteria
  • Anti-Bacterial Agents
 

Citation

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Lee, C.-J., Liang, X., Chen, X., Zeng, D., Joo, S. H., Chung, H. S., … Zhou, P. (2011). Species-specific and inhibitor-dependent conformations of LpxC: implications for antibiotic design. Chem Biol, 18(1), 38–47. https://doi.org/10.1016/j.chembiol.2010.11.011
Lee, Chul-Jin, Xiaofei Liang, Xin Chen, Daina Zeng, Sang Hoon Joo, Hak Suk Chung, Adam W. Barb, et al. “Species-specific and inhibitor-dependent conformations of LpxC: implications for antibiotic design.Chem Biol 18, no. 1 (January 28, 2011): 38–47. https://doi.org/10.1016/j.chembiol.2010.11.011.
Lee C-J, Liang X, Chen X, Zeng D, Joo SH, Chung HS, et al. Species-specific and inhibitor-dependent conformations of LpxC: implications for antibiotic design. Chem Biol. 2011 Jan 28;18(1):38–47.
Lee, Chul-Jin, et al. “Species-specific and inhibitor-dependent conformations of LpxC: implications for antibiotic design.Chem Biol, vol. 18, no. 1, Jan. 2011, pp. 38–47. Pubmed, doi:10.1016/j.chembiol.2010.11.011.
Lee C-J, Liang X, Chen X, Zeng D, Joo SH, Chung HS, Barb AW, Swanson SM, Nicholas RA, Li Y, Toone EJ, Raetz CRH, Zhou P. Species-specific and inhibitor-dependent conformations of LpxC: implications for antibiotic design. Chem Biol. 2011 Jan 28;18(1):38–47.

Published In

Chem Biol

DOI

EISSN

1879-1301

Publication Date

January 28, 2011

Volume

18

Issue

1

Start / End Page

38 / 47

Location

United States

Related Subject Headings

  • Species Specificity
  • Sequence Homology, Amino Acid
  • Organic Chemistry
  • Models, Molecular
  • Ligands
  • Enzyme Inhibitors
  • Drug Design
  • Catalytic Domain
  • Bacteria
  • Anti-Bacterial Agents