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Structure-assisted discovery of an aminothiazole derivative as a lead molecule for inhibition of bacterial fatty-acid synthesis.

Pappenberger G, Schulz-Gasch T, Kusznir E, Müller F, Hennig M - Acta Crystallogr. D Biol. Crystallogr. (2007)

Bottom Line: The active site is accessible through an open conformation of the Phe392 side chain and no conformational changes are induced at the active site upon ligand binding.This represents a novel binding mode that differs from thiolactomycin or cerulenin interaction.The structural information on the protein-ligand interaction offers strategies for further optimization of this low-molecular-weight compound.

View Article: PubMed Central - HTML - PubMed

Affiliation: F. Hoffmann-La Roche Ltd, Pharma Research Discovery, CH-4070 Basel, Switzerland.

ABSTRACT
Fatty-acid synthesis in bacteria is of great interest as a target for the discovery of antibacterial compounds. The addition of a new acetyl moiety to the growing fatty-acid chain, an essential step in this process, is catalyzed by beta-ketoacyl-ACP synthase (KAS). It is inhibited by natural antibiotics such as cerulenin and thiolactomycin; however, these lack the requirements for optimal drug development. Structure-based biophysical screening revealed a novel synthetic small molecule, 2-phenylamino-4-methyl-5-acetylthiazole, that binds to Escherichia coli KAS I with a binding constant of 25 microM as determined by fluorescence titration. A 1.35 A crystal structure of its complex with its target reveals noncovalent interactions with the active-site Cys163 and hydrophobic residues of the fatty-acid binding pocket. The active site is accessible through an open conformation of the Phe392 side chain and no conformational changes are induced at the active site upon ligand binding. This represents a novel binding mode that differs from thiolactomycin or cerulenin interaction. The structural information on the protein-ligand interaction offers strategies for further optimization of this low-molecular-weight compound.

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Structures of cerulenin, thiolactomycin and 2-phenylamino-4-methyl-5-acetylthiazole.
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fig1: Structures of cerulenin, thiolactomycin and 2-phenylamino-4-methyl-5-acetylthiazole.

Mentions: Several novel inhibitors of bacterial KAS III protein have recently been reported (He & Reynolds, 2002 ▶; Daines et al., 2003 ▶; He et al., 2004 ▶; Nie et al., 2005 ▶), highlighting the ongoing efforts to target novel antibacterial drugs against KAS activity. KAS I is a particularly attractive target as it has already been validated through the action of two compounds from natural sources: cerulenin and thiolactomycin (Fig. 1 ▶). Both inhibit KAS I and KAS II but not KAS III activity (Price et al., 2001 ▶). Cerulenin (from Cephalosporium caerulens) has a reactive epoxy group that forms a covalent adduct with the active-site cysteine of KAS (Price et al., 2001 ▶; Vance et al., 1972 ▶; D’Agnolo et al., 1973 ▶; Moche et al., 1999 ▶). It is not a selective antibacterial, however, since it also inhibits the KAS function of the mammalian FAS multienzyme complex. The second compound, thiolactomycin, is a thiolactone from actinobacteria (Nocardia sp.) that reversibly inhibits bacterial KAS (Price et al., 2001 ▶; Nishida et al., 1986 ▶). It is active against a wide range of bacteria and other pathogens such as plasmodia and trypanosomes (Noto et al., 1982 ▶; Waller et al., 1998 ▶; Morita et al., 2000 ▶). It does not affect mammalian fatty-acid bio­synthesis (Hayashi et al., 1983 ▶) and in mice it protects against infections without toxic side effects (Miyakawa et al., 1982 ▶). However, problems in synthesis and with stability have prevented its use as an antibiotic drug (Heath et al., 2001 ▶). Thiolactomycin-derived compounds with improved properties are currently being explored as inhibitors of bacterial and mammalian KAS (Sakya et al., 2001 ▶; Douglas et al., 2002 ▶; McFadden et al., 2005 ▶). Recently, a novel compound from a natural source, platensimycin, was discovered to be a potent inhibitor of bacterial KAS I and KAS II, with antibiotic properties in animal models (Wang et al., 2006 ▶). However, it remains challenging to develop such complex natural products into drug molecules with the required efficacy, synthetic access and pharmacological properties.


Structure-assisted discovery of an aminothiazole derivative as a lead molecule for inhibition of bacterial fatty-acid synthesis.

Pappenberger G, Schulz-Gasch T, Kusznir E, Müller F, Hennig M - Acta Crystallogr. D Biol. Crystallogr. (2007)

Structures of cerulenin, thiolactomycin and 2-phenylamino-4-methyl-5-acetylthiazole.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2483479&req=5

fig1: Structures of cerulenin, thiolactomycin and 2-phenylamino-4-methyl-5-acetylthiazole.
Mentions: Several novel inhibitors of bacterial KAS III protein have recently been reported (He & Reynolds, 2002 ▶; Daines et al., 2003 ▶; He et al., 2004 ▶; Nie et al., 2005 ▶), highlighting the ongoing efforts to target novel antibacterial drugs against KAS activity. KAS I is a particularly attractive target as it has already been validated through the action of two compounds from natural sources: cerulenin and thiolactomycin (Fig. 1 ▶). Both inhibit KAS I and KAS II but not KAS III activity (Price et al., 2001 ▶). Cerulenin (from Cephalosporium caerulens) has a reactive epoxy group that forms a covalent adduct with the active-site cysteine of KAS (Price et al., 2001 ▶; Vance et al., 1972 ▶; D’Agnolo et al., 1973 ▶; Moche et al., 1999 ▶). It is not a selective antibacterial, however, since it also inhibits the KAS function of the mammalian FAS multienzyme complex. The second compound, thiolactomycin, is a thiolactone from actinobacteria (Nocardia sp.) that reversibly inhibits bacterial KAS (Price et al., 2001 ▶; Nishida et al., 1986 ▶). It is active against a wide range of bacteria and other pathogens such as plasmodia and trypanosomes (Noto et al., 1982 ▶; Waller et al., 1998 ▶; Morita et al., 2000 ▶). It does not affect mammalian fatty-acid bio­synthesis (Hayashi et al., 1983 ▶) and in mice it protects against infections without toxic side effects (Miyakawa et al., 1982 ▶). However, problems in synthesis and with stability have prevented its use as an antibiotic drug (Heath et al., 2001 ▶). Thiolactomycin-derived compounds with improved properties are currently being explored as inhibitors of bacterial and mammalian KAS (Sakya et al., 2001 ▶; Douglas et al., 2002 ▶; McFadden et al., 2005 ▶). Recently, a novel compound from a natural source, platensimycin, was discovered to be a potent inhibitor of bacterial KAS I and KAS II, with antibiotic properties in animal models (Wang et al., 2006 ▶). However, it remains challenging to develop such complex natural products into drug molecules with the required efficacy, synthetic access and pharmacological properties.

Bottom Line: The active site is accessible through an open conformation of the Phe392 side chain and no conformational changes are induced at the active site upon ligand binding.This represents a novel binding mode that differs from thiolactomycin or cerulenin interaction.The structural information on the protein-ligand interaction offers strategies for further optimization of this low-molecular-weight compound.

View Article: PubMed Central - HTML - PubMed

Affiliation: F. Hoffmann-La Roche Ltd, Pharma Research Discovery, CH-4070 Basel, Switzerland.

ABSTRACT
Fatty-acid synthesis in bacteria is of great interest as a target for the discovery of antibacterial compounds. The addition of a new acetyl moiety to the growing fatty-acid chain, an essential step in this process, is catalyzed by beta-ketoacyl-ACP synthase (KAS). It is inhibited by natural antibiotics such as cerulenin and thiolactomycin; however, these lack the requirements for optimal drug development. Structure-based biophysical screening revealed a novel synthetic small molecule, 2-phenylamino-4-methyl-5-acetylthiazole, that binds to Escherichia coli KAS I with a binding constant of 25 microM as determined by fluorescence titration. A 1.35 A crystal structure of its complex with its target reveals noncovalent interactions with the active-site Cys163 and hydrophobic residues of the fatty-acid binding pocket. The active site is accessible through an open conformation of the Phe392 side chain and no conformational changes are induced at the active site upon ligand binding. This represents a novel binding mode that differs from thiolactomycin or cerulenin interaction. The structural information on the protein-ligand interaction offers strategies for further optimization of this low-molecular-weight compound.

Show MeSH
Related in: MedlinePlus