Chemistry & Biology
Structures of LpxC/LPC-009 Complexes
Gennadios, H.A., and Christianson, D.W. (2006). Binding of uridine 50-diphos-
phate in the ‘‘basic patch’’ of the zinc deacetylase LpxC and implications for
substrate binding. Biochemistry 45, 15216–15223.
Pirrung, M.C., Tumey, L.N., McClerren, A.L., and Raetz, C.R.H. (2003). High-
throughput catch-and-release synthesis of oxazoline hydroxamates: struc-
ture-activity relationships in novel inhibitors of Escherichia coli LpxC: in vitro
enzyme inhibition and antibacterial properties. J. Am. Chem. Soc. 125,
1575–1586.
Gennadios, H.A., Whittington, D.A., Li, X., Fierke, C.A., and Christianson, D.W.
(2006). Mechanistic inferences from the binding of ligands to LpxC,
a
metal-dependent deacetylase. Biochemistry 45, 7940–7948.
Raetz, C.R.H. (1998). Enzymes of lipid A biosynthesis: targets for the design of
new antibiotics. Prog. Clin. Biol. Res. 397, 1–14.
Hernick, M., Gennadios, H.A., Whittington, D.A., Rusche, K.M., Christianson,
D.W., and Fierke, C.A. (2005). UDP-3-O-((R)-3-hydroxymyristoyl)-N-acetylglu-
cosamine deacetylase functions through a general acid-base catalyst pair
mechanism. J. Biol. Chem. 280, 16969–16978.
Raetz, C.R.H., Reynolds, C.M., Trent, M.S., and Bishop, R.E. (2007). Lipid A
modification systems in Gram-negative bacteria. Annu. Rev. Biochem. 76,
295–329.
Jackman, J.E., Fierke, C.A., Tumey, L.N., Pirrung, M., Uchiyama, T., Tahir,
S.H., Hindsgaul, O., and Raetz, C.R.H. (2000). 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. 275, 11002–11009.
Raju, B.G., O’Dowd, H., Gao, H., Patel, D.V., and Trias, J. (2010). N-hydroxya-
mide derivatives possessing antibacterial activity. (US patent 7,691,843 B2:
Pfizer Inc., NY).
Robins, L.I., Williams, A.H., and Raetz, C.R. (2009). Structural basis for the
sugar nucleotide and acyl-chain selectivity of Leptospira interrogans LpxA.
Biochemistry 48, 6191–6201.
Jackman, J.E., Raetz, C.R.H., and Fierke, C.A. (2001). Site-directed mutagen-
esis of the bacterial metalloamidase UDP-(3-O- acyl)-N-acetylglucosamine
deacetylase (LpxC): identification of the zinc binding site. Biochemistry 40,
514–523.
Shin, H., Gennadios, H.A., Whittington, D.A., and Christianson, D.W. (2007).
Amphipathic benzoic acid derivatives: synthesis and binding in the hydro-
phobic tunnel of the zinc deacetylase LpxC. Bioorg. Med. Chem. 15, 2617–
2623.
Kline, T., Andersen, N.H., Harwood, E.A., Bowman, J., Malanda, A., Endsley,
S., Erwin, A.L., Doyle, M., Fong, S., Harris, A.L., et al. (2002). Potent, novel
in vitro inhibitors of the Pseudomonas aeruginosa deacetylase LpxC. J. Med.
Chem. 45, 3112–3129.
Siddiqui, M.A., Mansoor, U.F., Reddy, P.A., and Madison, V.S. (2007).
Compounds for the treatment of inflamatory disorders and microbial diseases
(international patent application no. WO 2007/064749 A1: Schering
Corporation, NJ, USA).
Mansoor, U.F., Reddy, P., Adulla, P., and Siddiqui, M.A. (2008). Hydantoin
derivatives useful as antibacterial agents (international patent application no.
WO 2008/027466 A1: Schering Corporation).
Takashima, H., Suga, Y., Urabe, H., Tsuruta, R., Kotsubo, H., Oohori, R., and
Kawaguchi, Y. (2010). Novel hydroxamic acid derivative having naphthyridine-
N-oxide (international patent application no. WO 2010/024356 A1: Taisho
Pharmaceutical Co., LTD).
Mansoor, U.F., Reddy, P.A., and Siddiqui, M.A. (2010). Urea derivatives as
antibacterial agents (international patent application no. WO 2010/017060
A1: Scherring Coporation).
McClerren, A.L., Endsley, S., Bowman, J.L., Andersen, N.H., Guan, Z.,
Rudolph, J., and Raetz, C.R. (2005). A slow, tight-binding inhibitor of the
zinc-dependent deacetylase LpxC of lipid A biosynthesis with antibiotic
activity comparable to ciprofloxacin. Biochemistry 44, 16574–16583.
Whittington, D.A., Rusche, K.M., Shin, H., Fierke, C.A., and Christianson, D.W.
(2003). Crystal structure of LpxC, a zinc-dependent deacetylase essential for
endotoxin biosynthesis. Proc. Natl. Acad. Sci. USA 100, 8146–8150.
Wikler, M.A., Low, D.E., Cockerill, F.R., Sheehan, D.J., Craig, W.A., Tenover,
F.C., and Dudley, M.N. (2006). Methods for dilution antimicrobial susceptibility
tests for bacteria that grow aerobically: approved standard, Seventh ed.
(M7-A7). (Wayne, PA: Clinical and Laboratory Standards Institute).
McCoy, A.J., Grosse-Kunstleve, R.W., Adams, P.D., Winn, M.D., Storoni, L.C.,
and Read, R.J. (2007). Phaser crystallographic software. J. Appl. Crystallogr.
40, 658–674.
Mochalkin, I., Knafels, J.D., and Lightle, S. (2008). Crystal structure of LpxC
from Pseudomonas aeruginosa complexed with the potent BB-78485 inhibitor.
Protein Sci. 17, 450–457.
Williams, A.H., and Raetz, C.R. (2007). Structural basis for the acyl chain
selectivity and mechanism of UDP-N-acetylglucosamine acyltransferase.
Proc. Natl. Acad. Sci. USA 104, 13543–13550.
Moser, H., Lu, Q., Patten, P.A., Wang, D., Kasar, R., Kaldor, S., and Patterson,
B.D. (2008). Antibacterial agents (international patent application no. WO
2008/154642 A2: Achaogen, Inc., South San Francisco, CA).
Yoshinaga, M., Ushiki, Y., Tsuruta, R., Urabe, H., Tanikawa, T., Tanabe, K.,
Baba, Y., Yokotani, M., Kawaguchi, Y., Kotsubo, H., et al. (2008). Novel
hydroxamic acid derivative (international patent application no. WO 2008/
105515 A1: Taisho Pharmaceutical Co., LTD).
Nicolaou, K.C., Zipkin, R.E., and Petasis, N.A. (1982). The endiandric acid
cascade: electrocyclizations in organic synthesis. 3. ‘‘Biomimetic’’ approach
to endiandric acids A-G. Synthesis of precursors. J. Am. Chem. Soc. 104,
5558–5560.
Zwart, P.H., Afonine, P.V., Grosse-Kunstleve, R.W., Hung, L.W., Ioerger, T.R.,
McCoy, A.J., McKee, E., Moriarty, N.W., Read, R.J., Sacchettini, J.C., et al.
(2008). Automated structure solution with the PHENIX suite. Methods Mol.
Biol. 426, 419–435.
Otwinowski, Z., and Minor, W. (1997). Processing of x-ray diffraction data
collected in oscillation mode. Methods Enzymol. 276, 301–326.
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