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PDBsum entry 3frd
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Oxidoreductase
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PDB id
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3frd
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References listed in PDB file
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Key reference
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Title
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Increased hydrophobic interactions of iclaprim with staphylococcus aureus dihydrofolate reductase are responsible for the increase in affinity and antibacterial activity.
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Authors
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C.Oefner,
M.Bandera,
A.Haldimann,
H.Laue,
H.Schulz,
S.Mukhija,
S.Parisi,
L.Weiss,
S.Lociuro,
G.E.Dale.
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Ref.
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J Antimicrob Chemother, 2009,
63,
687-698.
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PubMed id
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Abstract
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OBJECTIVES: Iclaprim is a novel 2,4-diaminopyrimidine that exhibits potent,
rapid bactericidal activity against major Gram-positive pathogens, including
methicillin-susceptible Staphylococcus aureus and methicillin-resistant S.
aureus, and is currently in clinical development for the treatment of
complicated skin and skin structure infections. An understanding of the known
mechanism of resistance to trimethoprim led to the design of this new inhibitor,
with improved affinity towards dihydrofolate reductase (DHFR) from S. aureus and
clinically useful activity against S. aureus including isolates resistant to
trimethoprim. The objective of this study was to characterize the mode of action
of iclaprim and its inhibitory properties against DHFR. METHODS: The mode of
action of iclaprim was assessed by enzymatic analysis, direct binding studies,
macromolecular synthesis profiles, synergy and antagonism studies to define its
role as an inhibitor of DHFR. The binding properties of iclaprim to DHFR were
compared with those of trimethoprim by X-ray crystallography. RESULTS: The
enzymatic properties, direct binding and X-ray crystallographic studies
delineated the mode of interaction with DHFR and the reason for the increased
affinity of iclaprim towards the enzyme. The effect of iclaprim on bacterial
physiology suggests that iclaprim behaves as a classical antibacterial DHFR
inhibitor, as previously documented for trimethoprim. CONCLUSIONS: Iclaprim
binds and inhibits bacterial DHFR in a similar manner to trimethoprim. However,
the increased hydrophobic interactions between iclaprim and DHFR account for
increased affinity and, unlike trimethoprim, enable iclaprim to inhibit even the
resistant enzyme with nanomolar affinity, thus overcoming the mechanism of
trimethoprim resistance. The increased antibacterial activity and lower
propensity for resistance make iclaprim a clinically promising and useful
inhibitor.
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