Molecular basis for triclosan activity involves a flipping loop in the active site

Qiu, Xiayang; Janson, Cheryl A.; Court, Robert; Smyth, Martin G.; Payne, D. J.; Abdel-Meguid, Sherin S.

doi:10.1110/ps.8.11.2529

Cited by 108 publications

(76 citation statements)

References 17 publications

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“…In vitro, platensimycin binds to FabF relatively weakly, which led to the discovery that it preferentially targets the acyl-thioester intermediate of the FabF pathway (paralleling the cases of isoniazid [10] and triclosan [11], which act through binding with a FabI-NAD reaction intermediates). In a crystal structure of a Cys-163-Gln FabF mutant, which simulates this intermediate, platensimycin was observed to bind at the active site of FabF with the carboxylic acid group lying in the malonate binding site coplanar with the amide sidechain of Gln163 (Fig 3).…”

Section: New Natural Product Inhibitors Of Fatty Acid Biosynthesismentioning

confidence: 99%

Antibacterial targets in fatty acid biosynthesis

Wright

Reynolds

2007

Current Opinion in Microbiology

171

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SummaryThe fatty acid biosynthesis pathway is an attractive but still largely unexploited target for development of new anti-bacterial agents. The extended use of the anti-tuberculosis drug isoniazid and the antiseptic triclosan, which are inhibitors of fatty acid biosynthesis, validates this pathway as a target for anti-bacterial development. Differences in subcellular organization of the bacterial and eukaryotic multi-enzyme fatty acid synthase systems offer the prospect of inhibitors with host vs. target specificity. Platensimycin, platencin, and phomallenic acids, newly discovered natural product inhibitors of the condensation steps in fatty acid biosynthesis, represent new classes of compounds with antibiotic potential. An almost complete catalogue of crystal structures for the enzymes of the type II fatty acid biosynthesis pathway can now be exploited in the rational design of new inhibitors, as well as the recently published crystal structures of type I FAS complexes.

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Section: New Natural Product Inhibitors Of Fatty Acid Biosynthesismentioning

confidence: 99%

Antibacterial targets in fatty acid biosynthesis

Wright

Reynolds

2007

Current Opinion in Microbiology

171

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“…FabH, a β-ketoacyl-acyl carrier protein synthase, is the bacterial condensing enzyme in Gram-positive and Gram-negative bacteria that initiates the cycle by catalyzing the first condensation step between acetyl-CoA and malonyl-ACP (139,140). Mycolic acid, one of the structurally largest fatty acids found in nature, is a vital cell wall component of the human tuberculosis strain of Mycobacterium tuberculosis.…”

Section: Thiolactomycin : Bacterial Fatty Acid Synthesis Inhibitormentioning

confidence: 99%

Efforts Towards the Development of New Antitubercular Agents: Potential for Thiolactomycin Based Compounds

et al. 2008

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Development of new chemotherapeutic drugs is the need of the hour to improve tuberculosis control, particularly in the developing world. In the last fourty years no new compound has been brought to the market for the treatment of tuberculosis. However, in recent years there is an enhanced activity in the research and development of new drugs for TB. Some compounds are presently in clinical development, while others are being investigated pre-clinically in an attempt to explore new molecules for the target based treatment of TB. Simultaneously some new targets are being identified and validated for their practical usefulness. Structures based on thiolactomycin could have considerable potential in the development of target based anti-TB agents. The present review provides an overview of the drugs that are being clinically used and the compounds that are in advanced stages of clinical as well as preclinical studies. We have also attempted to highlight the efforts that are being made in the development of new molecules based on thiolactomycin as lead compound, including studies from this laboratory.

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“…8 Many biochemical studies for the triclosan activity have been performed on the wild-type (WT) and mutated E. coli ENRs. [8][9][10][11][12][13][14][15][16] And as new bacterial ENR inhibitors, many ligands have been tested for their inhibitory activities. [17][18][19][20][21] At first in 1996 Rice's group used diazaborine derivatives as the antibacterial candidate ligand.…”

Section: Introductionmentioning

confidence: 99%

“…2,17 But these ligands are known to be toxic compounds, and it was investigated on molecular basis study that a flipping loop (I192-S198) of E. coli ENR is involved in the active site with triclosan. 14 In 2001 Heerding's group reported that the 1,4-disubstituted imidazoles are critical and effective inhibitors to FabI activity, 18 and Seefeld's group tested 2,9-disubstituted 1,2,3,4-tetrahydropyrido [3,4-b] It is very important to understand the functional groups and structures of good ligands and the important amino acid residues of the active site of ENR where the ligands would bind with different binding efficacies. Detailed understanding of the structure and energy relationship of these ENR inhibitors could help the design of new and improved ENR inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Understanding Drug-Protein Interactions in Escherichia coli FabI and Various FabI Inhibitor Complexes

Lee

Singh²

2011

Bulletin of the Korean Chemical Society

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Many ligands have been experimentally designed and tested for their activities as inhibitors against bacterial enoyl-ACP reductase (FabI), ENR. Here the binding energies of the reported ligands with the E. coli ENR-NAD + were calculated, analyzed and compared, and their molecular dynamics (MD) simulation study was performed. IDN, ZAM and AYM ligands were calculated to have larger binding energies than TCL and IDN has the largest binding energy among the considered ligands (TCL, S54, E26, ZAM, AYM and IDN). The contribution of residues to the ligand binding energy is larger in E. coli ENR-NAD + -IDN than in E. coli ENR-NAD + -TCL, while the contribution of NAD + is smaller for IDN than for TCL. The large-size ligands having considerable interactions with residues and NAD + have many effective functional groups such as aromatic π rings, acidic hydroxyl groups, and polarizable amide carbonyl groups in common. The cation-π interactions have large binding energies, positively charged residues strongly interact with polarisable amide carbonyl group, and the acidic phenoxyl group has strong H-bond interactions. The residues which have strong interactions with the ligands in common are Y146, Y156, M159 and K163. This study of the reported inhibitor candidates is expected to assist the design of feasible ENR inhibitors.

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Molecular basis for triclosan activity involves a flipping loop in the active site

Cited by 108 publications

References 17 publications

Antibacterial targets in fatty acid biosynthesis

Antibacterial targets in fatty acid biosynthesis

Efforts Towards the Development of New Antitubercular Agents: Potential for Thiolactomycin Based Compounds

Understanding Drug-Protein Interactions in Escherichia coli FabI and Various FabI Inhibitor Complexes

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