Antibacterial Drug Discovery Targeting the Lipopolysaccharide Biosynthetic Enzyme LpxC.

The enzyme LpxC (UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase) is broadly conserved across Gram-negative bacteria and is essential for synthesis of lipid A, the membrane anchor of the lipopolysaccharides (LPSs), which are a major component of the outer membrane in nearly all Gram-negative bacteria. LpxC has been the focus of target-directed antibiotic discovery projects in numerous pharmaceutical and academic groups for more than 20 years. Despite intense effort, no LpxC inhibitor has been approved for therapeutic use, and only one has yet reached human studies. This article will summarize the history of LpxC as a drug target and the parallel history of research on LpxC biology. Both academic and industrial researchers have used LpxC inhibitors as tool compounds, leading to increased understanding of the differing mechanisms for regulation of LPS synthesis in Escherichia coli and Pseudomonas aeruginosa.

[1]  Peter J Tonge,et al.  Translating slow-binding inhibition kinetics into cellular and in vivo effects. , 2015, Nature chemical biology.

[2]  シャポー ガエル,et al.  1,2-Dihydro-3H-pyrrolo [1,2-c] imidazol-3-one derivatives and their use as antibacterial agents , 2015 .

[3]  S. Andrews,et al.  A Complete Pathway Model for Lipid A Biosynthesis in Escherichia coli , 2015, PloS one.

[4]  크리스띠앙 위브슈웨를랭,et al.  Antibacterial 1h-indazole and 1h-indole derivatives , 2014 .

[5]  Matthew D. Miller,et al.  Synthesis, Structure, and SAR of Tetrahydropyran-Based LpxC Inhibitors. , 2014, ACS medicinal chemistry letters.

[6]  M. Kuhn,et al.  LpxC Inhibitors as New Antibacterial Agents and Tools for Studying Regulation of Lipid A Biosynthesis in Gram-Negative Pathogens , 2014, mBio.

[7]  E. Toone,et al.  Structural basis of the promiscuous inhibitor susceptibility of Escherichia coli LpxC. , 2014, ACS chemical biology.

[8]  E. Toone,et al.  Synthesis, structure, and antibiotic activity of aryl-substituted LpxC inhibitors. , 2013, Journal of medicinal chemistry.

[9]  Matthew D. Miller,et al.  Exploring the UDP pocket of LpxC through amino acid analogs. , 2013, Bioorganic & medicinal chemistry letters.

[10]  Daina Zeng,et al.  Mutants Resistant to LpxC Inhibitors by Rebalancing Cellular Homeostasis* , 2013, The Journal of Biological Chemistry.

[11]  V. Shanmugasundaram,et al.  Heterocyclic methylsulfone hydroxamic acid LpxC inhibitors as Gram-negative antibacterial agents. , 2012, Bioorganic & medicinal chemistry letters.

[12]  M. Adams,et al.  Inhibition of LpxC Protects Mice from Resistant Acinetobacter baumannii by Modulating Inflammation and Enhancing Phagocytosis , 2012, mBio.

[13]  V. Shanmugasundaram,et al.  Pyridone methylsulfone hydroxamate LpxC inhibitors for the treatment of serious gram-negative infections. , 2012, Journal of medicinal chemistry.

[14]  V. Shanmugasundaram,et al.  Potent inhibitors of LpxC for the treatment of Gram-negative infections. , 2012, Journal of medicinal chemistry.

[15]  W. Dowhan.  The Raetz pathway for lipid A biosynthesis: Christian Rudolf Hubert Raetz, M.D., PH.D. 1946-2011. , 2012, Glycobiology.

[16]  W. Dowhan.  The Raetz Pathway for Lipid A Biosynthesis: Christian Rudolf Hubert Raetz, MD PhD, 1946–2011 , 2011, Journal of Lipid Research.

[17]  J. Walker,et al.  Mechanisms Decreasing In Vitro Susceptibility to the LpxC Inhibitor CHIR-090 in the Gram-Negative Pathogen Pseudomonas aeruginosa , 2011, Antimicrobial Agents and Chemotherapy.

[18]  R. Hill,et al.  The Lipid A Assembly Pathway: The Work of Christian Raetz , 2011, The Journal of Biological Chemistry.

[19]  P. Orth,et al.  Design and synthesis of potent Gram-negative specific LpxC inhibitors. , 2011, Bioorganic & medicinal chemistry letters.

[20]  Pei Zhou,et al.  Species-specific and inhibitor-dependent conformations of LpxC: implications for antibiotic design. , 2011, Chemistry & biology.

[21]  P. Zhou,et al.  Syntheses, structures and antibiotic activities of LpxC inhibitors based on the diacetylene scaffold. , 2011, Bioorganic & medicinal chemistry.

[22]  F. Narberhaus,et al.  Control of Lipopolysaccharide Biosynthesis by FtsH-Mediated Proteolysis of LpxC Is Conserved in Enterobacteria but Not in All Gram-Negative Bacteria , 2010, Journal of bacteriology.

[23]  Jian Li,et al.  Colistin Resistance in Acinetobacter baumannii Is Mediated by Complete Loss of Lipopolysaccharide Production , 2010, Antimicrobial Agents and Chemotherapy.

[24]  C. Raetz,et al.  Antimicrobial Activity of CHIR-090, an Inhibitor of Lipopolysaccharide Biosynthesis, against the Burkholderia cepacia Complex , 2010, Antimicrobial Agents and Chemotherapy.

[25]  T. Silhavy,et al.  Transport of lipopolysaccharide across the cell envelope: the long road of discovery , 2009, Nature Reviews Microbiology.

[26]  C. Bertozzi,et al.  Uridine-based inhibitors as new leads for antibiotics targeting Escherichia coli LpxC. , 2009, Biochemistry.

[27]  I. Mochalkin,et al.  Crystal structure of LpxC from Pseudomonas aeruginosa complexed with the potent BB‐78485 inhibitor , 2008, Protein science : a publication of the Protein Society.

[28]  Pei Zhou,et al.  Structure of the deacetylase LpxC bound to the antibiotic CHIR-090: Time-dependent inhibition and specificity in ligand binding , 2007, Proceedings of the National Academy of Sciences.

[29]  Pei Zhou,et al.  Inhibition of lipid A biosynthesis as the primary mechanism of CHIR-090 antibiotic activity in Escherichia coli. , 2007, Biochemistry.

[30]  M. Pirrung,et al.  Molecular Validation of LpxC as an Antibacterial Drug Target in Pseudomonas aeruginosa , 2006, Antimicrobial Agents and Chemotherapy.

[31]  F. Narberhaus,et al.  The C‐terminal end of LpxC is required for degradation by the FtsH protease , 2006, Molecular microbiology.

[32]  J. Rudolph,et al.  A slow, tight-binding inhibitor of the zinc-dependent deacetylase LpxC of lipid A biosynthesis with antibiotic activity comparable to ciprofloxacin. , 2005, Biochemistry.

[33]  N. Munshi,et al.  Novel hydroxamic acid-derived HDAC inhibitor LBH589 potently activates intrinsic and extrinsic apoptotic pathways, and induces tubulin hyperacetylation in multiple myeloma. , 2005 .

[34]  Brian E. Coggins,et al.  Structure of the LpxC deacetylase with a bound substrate-analog inhibitor , 2003, Nature Structural Biology.

[35]  C. Fierke,et al.  Crystal structure of LpxC, a zinc-dependent deacetylase essential for endotoxin biosynthesis , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[36]  N. Andersen,et al.  Potent, novel in vitro inhibitors of the Pseudomonas aeruginosa deacetylase LpxC. , 2002, Journal of medicinal chemistry.

[37]  S. Chandler,et al.  Antibacterial Activities and Characterization of Novel Inhibitors of LpxC , 2002, Antimicrobial Agents and Chemotherapy.

[38]  J. Shimada.  [Antibacterial agents]. , 2002, Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine.

[39]  ウィッタカー，マーク,et al.  Hydroxamic acid derivatives as antibacterial agents , 1999 .

[40]  S. E. D. Laszlo,et al.  Carbohydroxamido-oxazolidines: antibacterial agents that target lipid A biosynthesis. , 1999, Bioorganic & medicinal chemistry letters.

[41]  C. Fierke,et al.  Balanced biosynthesis of major membrane components through regulated degradation of the committed enzyme of lipid A biosynthesis by the AAA protease FtsH (HflB) in Escherichia coli , 1999, Molecular microbiology.

[42]  A. Patchett,et al.  Antibacterial Agents That Inhibit Lipid A Biosynthesis , 1996, Science.

[43]  J. Lutkenhaus,et al.  Regulation of UDP-3-O-[R-3-hydroxymyristoyl]-N-acetylglucosamine Deacetylase in Escherichia coli , 1996, The Journal of Biological Chemistry.

[44]  C. Raetz,et al.  The envA Permeability/Cell Division Gene of Escherichia coli Encodes the Second Enzyme of Lipid A Biosynthesis , 1995, The Journal of Biological Chemistry.

[45]  S. Galloway,et al.  UDP-N-acetylglucosamine acyltransferase of Escherichia coli. The first step of endotoxin biosynthesis is thermodynamically unfavorable. , 1993, The Journal of biological chemistry.

[46]  C. Raetz,et al.  Bacterial endotoxins: extraordinary lipids that activate eucaryotic signal transduction , 1993, Journal of bacteriology.

[47]  R. Misra,et al.  Identification and characterization of a new gene of Escherichia coli K-12 involved in outer membrane permeability. , 1989, Genetics.

[48]  J. Lutkenhaus,et al.  Sequence analysis, transcriptional organization, and insertional mutagenesis of the envA gene of Escherichia coli , 1987, Journal of bacteriology.

[49]  W. Zimmermann.  Penetration of beta-lactam antibiotics into their target enzymes in Pseudomonas aeruginosa: comparison of a highly sensitive mutant with its parent strain , 1980, Antimicrobial Agents and Chemotherapy.

[50]  P. D. Rick,et al.  Mechanism of assembly of the outer membrane of Salmonella typhimurium. Translocation and integration of an incomplete mutant lipid A into the outer membrane. , 1980, The Journal of biological chemistry.

[51]  L. Leive.  THE BARRIER FUNCTION OF THE GRAM‐NEGATIVE ENVELOPE , 1974, Annals of the New York Academy of Sciences.

[52]  M. Osborn,et al.  Mechanism of assembly of the outer membrane of Salmonella typhimurium. Site of synthesis of lipopolysaccharide. , 1972, The Journal of biological chemistry.

[53]  S. Normark,et al.  Mutant of Escherichia coli with Anomalous Cell Division and Ability to Decrease Episomally and Chromosomally Mediated Resistance to Ampicillin and Several Other Antibiotics , 1969, Journal of bacteriology.