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PDBsum entry 4idj
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Immune system
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PDB id
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4idj
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Contents |
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276 a.a.
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224 a.a.
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214 a.a.
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References listed in PDB file
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Key reference
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Title
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Mechanism of action and in vivo efficacy of a human-Derived antibody against staphylococcus aureus α-Hemolysin.
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Authors
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D.Foletti,
P.Strop,
L.Shaughnessy,
A.Hasa-Moreno,
M.G.Casas,
M.Russell,
C.Bee,
S.Wu,
A.Pham,
Z.Zeng,
J.Pons,
A.Rajpal,
D.Shelton.
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Ref.
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J Mol Biol, 2013,
425,
1641-1654.
[DOI no: ]
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PubMed id
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Abstract
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The emergence and spread of multi-drug-resistant strains of Staphylococcus
aureus in hospitals and in the community emphasize the urgency for the
development of novel therapeutic interventions. Our approach was to evaluate the
potential of harnessing the human immune system to guide the development of
novel therapeutics. We explored the role of preexisting antibodies against S.
aureus α-hemolysin in the serum of human individuals by isolating and
characterizing one antibody with a remarkably high affinity to α-hemolysin. The
antibody provided protection in S. aureus pneumonia, skin, and bacteremia mouse
models of infection and also showed therapeutic efficacy when dosed up to 18 h
post-infection in the pneumonia model. Additionally, in pneumonia and bacteremia
animal models, the therapeutic efficacy of the α-hemolysin antibody appeared
additive to the antibiotic linezolid. To better understand the mechanism of
action of this isolated antibody, we solved the crystal structure of the
α-hemolysin:antibody complex. To our knowledge, this is the first report of the
crystal structure of the α-hemolysin monomer. The structure of the complex
shows that the antibody binds α-hemolysin between the cap and the rim domains.
In combination with biochemical data, the structure suggests that the antibody
neutralizes the activity of the toxin by preventing binding to the plasma
membrane of susceptible host cells. The data presented here suggest that
protective antibodies directed against S. aureus molecules exist in some
individuals and that such antibodies have a therapeutic potential either alone
or in combination with antibiotics.
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