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PDBsum entry 2gfx
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References listed in PDB file
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Key reference
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Title
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Platensimycin is a selective fabf inhibitor with potent antibiotic properties.
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Authors
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J.Wang,
S.M.Soisson,
K.Young,
W.Shoop,
S.Kodali,
A.Galgoci,
R.Painter,
G.Parthasarathy,
Y.S.Tang,
R.Cummings,
S.Ha,
K.Dorso,
M.Motyl,
H.Jayasuriya,
J.Ondeyka,
K.Herath,
C.Zhang,
L.Hernandez,
J.Allocco,
A.Basilio,
J.R.Tormo,
O.Genilloud,
F.Vicente,
F.Pelaez,
L.Colwell,
S.H.Lee,
B.Michael,
T.Felcetto,
C.Gill,
L.L.Silver,
J.D.Hermes,
K.Bartizal,
J.Barrett,
D.Schmatz,
J.W.Becker,
D.Cully,
S.B.Singh.
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Ref.
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Nature, 2006,
441,
358-361.
[DOI no: ]
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PubMed id
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Abstract
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Bacterial infection remains a serious threat to human lives because of emerging
resistance to existing antibiotics. Although the scientific community has avidly
pursued the discovery of new antibiotics that interact with new targets, these
efforts have met with limited success since the early 1960s. Here we report the
discovery of platensimycin, a previously unknown class of antibiotics produced
by Streptomyces platensis. Platensimycin demonstrates strong, broad-spectrum
Gram-positive antibacterial activity by selectively inhibiting cellular lipid
biosynthesis. We show that this anti-bacterial effect is exerted through the
selective targeting of beta-ketoacyl-(acyl-carrier-protein (ACP)) synthase I/II
(FabF/B) in the synthetic pathway of fatty acids. Direct binding assays show
that platensimycin interacts specifically with the acyl-enzyme intermediate of
the target protein, and X-ray crystallographic studies reveal that a specific
conformational change that occurs on acylation must take place before the
inhibitor can bind. Treatment with platensimycin eradicates Staphylococcus
aureus infection in mice. Because of its unique mode of action, platensimycin
shows no cross-resistance to other key antibiotic-resistant strains tested,
including methicillin-resistant S. aureus, vancomycin-intermediate S. aureus and
vancomycin-resistant enterococci. Platensimycin is the most potent inhibitor
reported for the FabF/B condensing enzymes, and is the only inhibitor of these
targets that shows broad-spectrum activity, in vivo efficacy and no observed
toxicity.
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Figure 1.
Figure 1: Characterization of platensimycin. a, Structure of
platensimycin. b, In vivo studies on platensimycin. Dosing at 50
 g
h^-1 showed small decrease in viable S. aureus cells from the
infected kidney. However, a 10^4–10^5 fold decrease (4 and 5
log reduction) were achieved with 100 and 150 g
h^-1, respectively. Dosing at 150 g
h^-1 showed 40% of the kidneys with no viable S. aureus, whereas
dosing at 100 g
h^-1 showed 20% of the kidneys without detectable viable S.
aureus. Error bars indicate s.d. observed with five infected
mice. The results were confirmed by a repeat experiment. c,
Whole-cell labelling assay^16 with platensimycin. The assay was
performed with a serial dilution of platensimycin, starting at
500 g
ml^-1. Platensimycin showed no significant inhibition against
syntheses of DNA (open circles), cell wall (filled triangles),
protein (open squares) and RNA (open triangles) but greatly
inhibited phospholipid synthesis (filled circles), providing an
IC[50] value of 0.1 g
ml^-1. Error bars indicate s.d. for three individual
experiments. d, Direct binding assay results of
[^3H]dihydroplatensimycin and E. coli FabF (ecFabF) in the
presence and absence of n-dodecanoyl coenzyme A (lauroyl-CoA;
C[12]-CoA) and the C163Q mutant protein. Error bars indicate
s.d. observed with six replicate wells. Experimental details are
given in Supplementary Information.
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Figure 2.
Figure 2: Interactions of platensimycin with ecFabF(C163Q) and
comparison with the apo structure. a, Superposition of
platensimycin (yellow, thicker sticks) on ecFabF, with
thiolactomycin (green) and cerulenin (cyan) shown for reference.
Side chains discussed in the text are labelled and coloured as
described above. The side chains from apo ecFabF are coloured
magenta. b, Interactions between the benzoic acid ring of
platensimycin (yellow) and ecFabF(C163Q). Side chains from the
protein discussed in the text are labelled and coloured green.
c, Interactions of ecFabF with the amide linker and ketolide of
platensimycin. The colour scheme is the same as in b. d, The
solvent-accessible surface area of FabF, coloured according to
electrostatic potential. Platensimycin is depicted as a stick
figure and coloured yellow, and is shown to be partly exposed to
solvent. Platensimycin buries 345 Å^2 of
solvent-accessible surface area on ecFabF, as calculated with
areaimol^24,25. Of that surface area, 122 Å^2 is a direct
result of the ketolide portion of the molecule, highlighting its
important contribution to platensimycin binding. Significant
interatomic distances (in ångströms) are marked in b
and c with red dashed lines and numbers.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nature
(2006,
441,
358-361)
copyright 2006.
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