Lipid a biosynthesis of multidrug-resistant pathogens - A novel drug target

Current Pharmaceutical Design

Volumn 19, Issue 36, 2013, Pages 6534-6550

  Lee, Chang Ro ^a   Lee, Jung Hun ^a   Jeong, Byeong Chul ^a   Lee, Sang Hee ^a  

^a Myong Ji University   (South Korea)

Author keywords

Acyltransferase; Chemotherapy; Deacetylase; Lipid A biosynthesis; Multidrug resistant pathogens

Indexed keywords

ANTIBIOTIC AGENT; BB 78484; BB 78485; CHIR 090; CHR 12; HYDROLASE; L 161240; LIPID A; LPC 009; LPC 011; LPC 012; LPC 013; LPC 054; RJPXD 33; TU 514; TU 521; UNCLASSIFIED DRUG; URIDINE DIPHOSPHATE 3 O (3 HYDROXYACYL) N ACETYLGLUCOSAMINE DEACETYLASE; URIDINE DIPHOSPHATE 3 O (3 HYDROXYACYL) N ACETYLTRANSFERASE; URIDINE DIPHOSPHATE N ACETYLGLUCOSAMINE ACYLTRANSFERASE;

ANTIBACTERIAL ACTIVITY; ARABIDOPSIS THALIANA; CRYSTAL STRUCTURE; DRUG DESIGN; DRUG SCREENING; DRUG STRUCTURE; DRUG TARGETING; ENZYME ACTIVITY; ESCHERICHIA COLI; GRAM NEGATIVE BACTERIUM; IC 50; LEPTOSPIRA INTERROGANS; MINIMUM INHIBITORY CONCENTRATION; NONHUMAN; PRIORITY JOURNAL; REVIEW; RHIZOBIUM LEGUMINOSARUM;

ACYLTRANSFERASES; AMIDOHYDROLASES; ANIMALS; DRUG DESIGN; DRUG RESISTANCE, MULTIPLE; ENZYME INHIBITORS; GRAM-NEGATIVE BACTERIA; GRAM-NEGATIVE BACTERIAL INFECTIONS; HUMANS; LIPID A;

EID: 84887980311     PISSN: 13816128     EISSN: 18734286     Source Type: Journal    
DOI: 10.2174/13816128113199990494     Document Type: Review

References (80)

1. Levy SB, Marshall B. Antibacterial resistance worldwide: causes, challenges and responses. Nat Med 2004; 10: S122-9.
2. Paterson DL. Resistance in gram-negative bacteria: Enterobacteriaceae. Am J Infect Control 2006; 34: S20-8; discussion S64-73.
3. Lee JH, Bae IK, Lee SH. New definitions of extended-spectrum beta-lactamase conferring worldwide emerging antibiotic resistance. Med Res Rev 2012; 32: 216-32.
4. Lee JH, Jeong SH, Cha SS, Lee SH. New disturbing trend in antimicrobial resistance of gram-negative pathogens. PLoS Pathog 2009; 5: e1000221.
5. Vergidis PI, Falagas ME. Multidrug-resistant Gram-negative bacterial infections: the emerging threat and potential novel treatment options. Curr Opin Investig Drugs 2008; 9: 176-83.
6. Lee JH, Jeong SH, Cha S-S, Lee SH. A lack of drugs for antibioticresistant Gram-negative bacteria. Nat Rev Drug Discov 2007; 6: doi: 10. 1038/nrd2201-c1.
7. Raetz CR, Whitfield C. Lipopolysaccharide endotoxins. Annu Rev Biochem 2002; 71: 635-700.
8. Wyckoff TJ, Raetz CR, Jackman JE. Antibacterial and antiinflammatory agents that target endotoxin. Trends Microbiol 1998; 6: 154-9.
9. Nikaido H, Vaara M. Molecular basis of bacterial outer membrane permeability. Microbiol Rev 1985; 49: 1-32.
10. Galloway SM, Raetz CR. A mutant of Escherichia coli defective in the first step of endotoxin biosynthesis. J Biol Chem 1990; 265: 6394-402.
11. Raetz CR. Bacterial endotoxins: extraordinary lipids that activate eucaryotic signal transduction. J Bacteriol 1993; 175: 5745-53.
12. Vuorio R, Vaara M. The lipid A biosynthesis mutation lpxA2 of Escherichia coli results in drastic antibiotic supersusceptibility. Antimicrob Agents Chemother 1992; 36: 826-9.
13. Okuda S, Freinkman E, Kahne D. Cytoplasmic ATP hydrolysis powers transport of lipopolysaccharide across the periplasm in E. coli. Science 2012; 338: 1214-7.
14. Onishi HR, Pelak BA, Gerckens LS, et al. Antibacterial agents that inhibit lipid A biosynthesis. Science 1996; 274: 980-2.
15. Anderson MS, Bull HG, Galloway SM, et al. UDP-Nacetylglucosamine acyltransferase of Escherichia coli. The first step of endotoxin biosynthesis is thermodynamically unfavorable. J Biol Chem 1993; 268: 19858-65.
16. Barb AW, Zhou P. Mechanism and inhibition of LpxC: an essential zinc-dependent deacetylase of bacterial lipid A synthesis. Curr Pharm Biotechnol 2008; 9: 9-15.
17. Bartling CM, Raetz CR. Steady-state kinetics and mechanism of LpxD, the N-acyltransferase of lipid A biosynthesis. Biochemistry 2008; 47: 5290-302.
18. Kelly TM, Stachula SA, Raetz CR, Anderson MS. The firA gene of Escherichia coli encodes UDP-3-O-(R-3-hydroxymyristoyl)-glucosamine N-acyltransferase. The third step of endotoxin biosynthesis. J Biol Chem 1993; 268: 19866-74.
19. Kim HJ, Lee CR, Kim M, Peterkofsky A, Seok YJ. Dephosphorylated NPr of the nitrogen PTS regulates lipid A biosynthesis by direct interaction with LpxD. Biochem Biophys Res Commun 2011; 409: 556-61.
20. Sorensen PG, Lutkenhaus J, Young K, Eveland SS, Anderson MS, Raetz CR. Regulation of UDP-3-O-[R-3-hydroxymyristoyl]-Nacetylglucosamine deacetylase in Escherichia coli. The second enzymatic step of lipid a biosynthesis. J Biol Chem 1996; 271: 25898-905.
21. Raetz CR, Roderick SL. A left-handed parallel [helix in the structure of UDP-N-acetylglucosamine acyltransferase. Science 1995; 270: 997-1000.
22. Williams AH, Immormino RM, Gewirth DT, Raetz CR. Structure of UDP-N-acetylglucosamine acyltransferase with a bound antibacterial pentadecapeptide. Proc Natl Acad Sci USA 2006; 103: 10877-82.
23. Williams AH, Raetz CR. Structural basis for the acyl chain selectivity and mechanism of UDP-N-acetylglucosamine acyltransferase. Proc Natl Acad Sci USA 2007; 104: 13543-50.
24. Badger J, Chie-Leon B, Logan C, et al. Structure determination of LpxA from the lipopolysaccharide-synthesis pathway of Acinetobacter baumannii. Acta Crystallogr Sect F Struct Biol Cryst Commun 2012; 68: 1477-81.
25. Robins LI, Williams AH, Raetz CR. Structural basis for the sugar nucleotide and acyl-chain selectivity of Leptospira interrogans LpxA. Biochemistry 2009; 48: 6191-201.
26. Joo SH, Chung HS, Raetz CR, Garrett TA. Activity and crystal structure of Arabidopsis thaliana UDP-N-acetylglucosamine acyltransferase. Biochemistry 2012; 51: 4322-30.
27. Beaman TW, Blanchard JS, Roderick SL. The conformational change and active site structure of tetrahydrodipicolinate Nsuccinyltransferase. Biochemistry 1998; 37: 10363-9.
28. Olsen LR, Roderick SL. Structure of the Escherichia coli GlmU pyrophosphorylase and acetyltransferase active sites. Biochemistry 2001; 40: 1913-21.
29. Wang XG, Olsen LR, Roderick SL. Structure of the lac operon galactoside acetyltransferase. Structure 2002; 10: 581-8.
30. Wyckoff TJ, Raetz CR. The active site of Escherichia coli UDP-Nacetylglucosamine acyltransferase. Chemical modification and sitedirected mutagenesis. J Biol Chem 1999; 274: 27047-55.
31. Wyckoff TJ, Lin S, Cotter RJ, Dotson GD, Raetz CR. Hydrocarbon rulers in UDP-N-acetylglucosamine acyltransferases. J Biol Chem 1998; 273: 32369-72.
32. Li C, Guan Z, Liu D, Raetz CR. Pathway for lipid A biosynthesis in Arabidopsis thaliana resembling that of Escherichia coli. Proc Natl Acad Sci USA 2011; 108: 11387-92.
33. Coggins BE, Li X, McClerren AL, Hindsgaul O, Raetz CR, Zhou P. Structure of the LpxC deacetylase with a bound substrate-analog inhibitor. Nat Struct Biol 2003; 10: 645-51.
34. Whittington DA, Rusche KM, Shin H, Fierke CA, Christianson DW. Crystal structure of LpxC, a zinc-dependent deacetylase essential for endotoxin biosynthesis. Proc Natl Acad Sci USA 2003; 100: 8146-50.
35. Jackman JE, Raetz CR, Fierke CA. UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase of Escherichia coli is a zinc metalloenzyme. Biochemistry 1999; 38: 1902-11.
36. Mochalkin I, Knafels JD, Lightle S. Crystal structure of LpxC from Pseudomonas aeruginosa complexed with the potent BB-78485 inhibitor. Protein Sci 2008; 17: 450-7.
37. Hernick M, Fierke CA. Zinc hydrolases: the mechanisms of zincdependent deacetylases. Arch Biochem Biophys 2005; 433: 71-84.
38. Jackman JE, Raetz CR, Fierke CA. Site-directed mutagenesis of the bacterial metalloamidase UDP-(3-O-acyl)-N-acetylglucosamine deacetylase (LpxC). Identification of the zinc binding site. Biochemistry 2001; 40: 514-23.
39. Hernick M, Gennadios HA, Whittington DA, Rusche KM, Christianson DW, Fierke CA. UDP-3-O-(R)-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase functions through a general acidbase catalyst pair mechanism. J Biol Chem 2005; 280: 16969-78.
40. Bartling CM, Raetz CR. Crystal structure and acyl chain selectivity of Escherichia coli LpxD, the N-acyltransferase of lipid A biosynthesis. Biochemistry 2009; 48: 8672-83.
41. Badger J, Chie-Leon B, Logan C, et al. The structure of LpxD from Pseudomonas aeruginosa at 1. 3 Å resolution. Acta Crystallogr Sect F Struct Biol Cryst Commun 2011; 67: 749-52.
42. Buetow L, Smith TK, Dawson A, Fyffe S, Hunter WN. Structure and reactivity of LpxD, the N-acyltransferase of lipid A biosynthesis. Proc Natl Acad Sci USA 2007; 104: 4321-6.
43. Badger J, Chie-Leon B, Logan C, et al. Structure determination of LpxD from the lipopolysaccharide-synthesis pathway of Acinetobacter baumannii. Acta Crystallogr Sect F Struct Biol Cryst Commun 2013; 69: 6-9.
44. Rund S, Lindner B, Brade H, Holst O. Structural analysis of the lipopolysaccharide from Chlamydia trachomatis serotype L2. J Biol Chem 1999; 274: 16819-24.
45. Cuny GD. A new class of UDP-3-O-(R-3-hydroxymyristol)-Nacetylglucosamine deacetylase (LpxC) inhibitors for the treatment of Gram-negative infections: PCT application WO 2008027466. Expert Opin Ther Pat 2009; 19: 893-9.
46. Zhang J, Zhang L, Li X, Xu W. UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) inhibitors: a new class of antibacterial agents. Curr Med Chem 2012; 19: 2038-50.
47. Chen MH, Steiner MG, de Laszlo SE, et al. Carbohydroxamidooxazolidines: antibacterial agents that target lipid A biosynthesis. Bioorg Med Chem Lett 1999; 9: 313-8.
48. Mdluli KE, Witte PR, Kline T, et al. Molecular validation of LpxC as an antibacterial drug target in Pseudomonas aeruginosa. Antimicrob Agents Chemother 2006; 50: 2178-84.
49. Jackman JE, Fierke CA, Tumey LN, et al. Antibacterial agents that target lipid A biosynthesis in gram-negative bacteria. Inhibition of diverse UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylases by substrate analogs containing zinc binding motifs. J Biol Chem 2000; 275: 11002-9.
50. Coggins BE, McClerren AL, Jiang L, et al. Refined solution structure of the LpxC-TU-514 complex and pKa analysis of an active site histidine: insights into the mechanism and inhibitor design. Biochemistry 2005; 44: 1114-26.
51. Cheng XC, Wang Q, Fang H, Xu WF. Role of sulfonamide group in matrix metalloproteinase inhibitors. Curr Med Chem 2008; 15: 368-73.
52. Clements JM, Coignard F, Johnson I, et al. Antibacterial activities and characterization of novel inhibitors of LpxC. Antimicrob Agents Chemother 2002; 46: 1793-9.
53. McClerren AL, Endsley S, Bowman JL, et al. A slow, tight-binding inhibitor of the zinc-dependent deacetylase LpxC of lipid A biosynthesis with antibiotic activity comparable to ciprofloxacin. Biochemistry 2005; 44: 16574-83.
54. Barb AW, McClerren AL, Snehelatha K, Reynolds CM, Zhou P, Raetz CR. Inhibition of lipid A biosynthesis as the primary mechanism of CHIR-090 antibiotic activity in Escherichia coli. Biochemistry 2007; 46: 3793-802.
55. Cole KE, Gattis SG, Angell HD, Fierke CA, Christianson DW. Structure of the metal-dependent deacetylase LpxC from Yersinia enterocolitica complexed with the potent inhibitor CHIR-090. Biochemistry 2011; 50: 258-65.
56. Barb AW, Jiang L, Raetz CR, Zhou P. Structure of the deacetylase LpxC bound to the antibiotic CHIR-090: Time-dependent inhibition and specificity in ligand binding. Proc Natl Acad Sci USA 2007; 104: 18433-8.
57. Lee CJ, Liang X, Chen X, et al. Species-specific and inhibitordependent conformations of LpxC: implications for antibiotic design. Chem Biol 2011; 18: 38-47.
58. Liang X, Lee CJ, Chen X, et al. Syntheses, structures and antibiotic activities of LpxC inhibitors based on the diacetylene scaffold. Bioorg Med Chem 2011; 19: 852-60.
59. Mansoor UF, Vitharana D, Reddy PA, et al. Design and synthesis of potent Gram-negative specific LpxC inhibitors. Bioorg Med Chem Lett 2011; 21: 1155-61.
60. Kalgutkar AS, Gardner I, Obach RS, et al. A comprehensive listing of bioactivation pathways of organic functional groups. Curr Drug Metab 2005; 6: 161-225.
61. Warmus JS, Quinn CL, Taylor C, et al. Structure based design of an in vivo active hydroxamic acid inhibitor of P. aeruginosa LpxC. Bioorg Med Chem Lett 2012; 22: 2536-43.
62. Brown MF, Reilly U, Abramite JA, et al. Potent inhibitors of LpxC for the treatment of Gram-negative infections. J Med Chem 2012; 55: 914-23.
63. McAllister LA, Montgomery JI, Abramite JA, et al. Heterocyclic methylsulfone hydroxamic acid LpxC inhibitors as Gram-negative antibacterial agents. Bioorg Med Chem Lett 2012; 22: 6832-8.
64. Montgomery JI, Brown MF, Reilly U, et al. Pyridone methylsulfone hydroxamate LpxC inhibitors for the treatment of serious gram-negative infections. J Med Chem 2012; 55: 1662-70.
65. Muri EM, Nieto MJ, Sindelar RD, Williamson JS. Hydroxamic acids as pharmacological agents. Curr Med Chem 2002; 9: 1631-53.
66. Tu G, Xu W, Huang H, Li S. Progress in the development of matrix metalloproteinase inhibitors. Curr Med Chem 2008; 15: 1388-95.
67. Mock WL, Cheng H. Principles of hydroxamate inhibition of metalloproteases: carboxypeptidase A. Biochemistry 2000; 39: 13945-52.
68. Bauvois B, Dauzonne D. Aminopeptidase-N/CD13 (EC 3. 4. 11. 2) inhibitors: chemistry, biological evaluations, and therapeutic prospects. Med Res Rev 2006; 26: 88-130.
69. Park JD, Kim DH. Reversed hydroxamate-bearing thermolysin inhibitors mimic a high-energy intermediate along the enzymecatalyzed proteolytic reaction pathway. Bioorg Med Chem Lett 2003; 13: 3161-6.
70. Pirrung MC, Tumey LN, Raetz CR, et al. Inhibition of the antibacterial target UDP-(3-O-acyl)-N-acetylglucosamine deacetylase (LpxC): isoxazoline zinc amidase inhibitors bearing diverse metal binding groups. J Med Chem 2002; 45: 4359-70.
71. Barb AW, Leavy TM, Robins LI, et al. Uridine-based inhibitors as new leads for antibiotics targeting Escherichia coli LpxC. Biochemistry 2009; 48: 3068-77.
72. Mansoor UF, Reddy PAP, Siddiqui MA. Hydantoin derivatives useful as antibacterial agents. 2008WO2008027466.
73. Shin H, Gennadios HA, Whittington DA, Christianson DW. Amphipathic benzoic acid derivatives: synthesis and binding in the hydrophobic tunnel of the zinc deacetylase LpxC. Bioorg Med Chem 2007; 15: 2617-23.
74. Buetow L, Dawson A, Hunter WN. The nucleotide-binding site of Aquifex aeolicus LpxC. Acta Crystallogr Sect F Struct Biol Cryst Commun 2006; 62: 1082-6.
75. Ghasemi JB, Safavi-Sohi R, Barbosa EG. 4D-LQTA-QSAR and docking study on potent Gram-negative specific LpxC inhibitors: a comparison to CoMFA modeling. Mol Divers 2012; 16: 203-13.
76. Langsdorf EF, Malikzay A, Lamarr WA, et al. Screening for antibacterial inhibitors of the UDP-3-O-(R-3-hydroxymyristoyl)-Nacetylglucosamine deacetylase (LpxC) using a high-throughput mass spectrometry assay. J Biomol Screen 2010; 15: 52-61.
77. Pradhan D, Priyadarshini V, Munikumar M, Swargam S, Umamaheswari A, Bitla A. Para-(benzoyl)-phenylalanine as a potential inhibitor against LpxC of Leptospira spp.: homology modeling, docking, and molecular dynamics study. J Biomol Struct Dyn 2013.
78. Lin L, Tan B, Pantapalangkoor P, et al. Inhibition of LpxC protects mice from resistant Acinetobacter baumannii by modulating inflammation and enhancing phagocytosis. MBio 2012; 3.
79. Benson RE, Gottlin EB, Christensen DJ, Hamilton PT. Intracellular expression of Peptide fusions for demonstration of protein essentiality in bacteria. Antimicrob Agents Chemother 2003; 47: 2875-81.
80. Jenkins RJ, Dotson GD. Dual targeting antibacterial peptide inhibitor of early lipid a biosynthesis. ACS Chem Biol 2012; 7: 1170-7.