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The reductase steps of the type II fatty acid synthase as antimicrobial targets

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Lipids

Abstract

The increasing of multidrug resistance of clinically important pathogens calls for the development of novel antibiotics with unexploited cellular targets. FA biosynthesis in bacteria is catalyzed by a group of highly conserved proteins known as the type II FA synthase (FAS II) system. Bacteria FAS II organization is distinct from its mammalian counterpart; thus the FAS II pathway offers several unique steps for selective inhibition by antibacterial agents. Some known antibiotics that target the FAS II system include triclosan, isoniazid, and thiolactomycin. Recent years have seen remarkable progress in the understanding of the genetics, biochemistry, and regulation of the FAS II system with the availability of the complete geome, sequence for many bacteria. Crystal structures of the FAS II pathway enzymes have been determined for not only the Escherichia coli model system but also other gram-netative and gram-positive pathogens. The protein structures have greatly facilitated structure-based design of novel inhibitors and the improvement of existing antibacterial agents. This review discusses new developments in the discovery of inhibitors that specifically target the two reductase steps of the FAS II system, β-ketoacyl-acyl carrier potein (ACP) reductase and enoyl-ACP reductase.

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Abbreviations

ACP:

acyl carrier protein

EGCG:

epigallocatechin gallate

FabG:

β-ketoacyl-ACP reductase

FabI:

enoyl-ACP reductase I

FabK:

enoyl-ACP reductase II

FabL:

enoyl-ACP reductase III

FAS I:

type I fatty acid synthase

FAS II:

type II fatty acid synthase

INH:

isoniazid acid hydrazide

SAR:

structure-activity relationship

Is:

temperature sensitive

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Author information

Authors and Affiliations

  1. Department of Molecular Sciences, University of Tennessee Health Science Center, 38163, Memphis, Tennessee

    Charles O. Rock

  2. Department of Infectious Diseases, Protein Science Division, St. Jude Children's Research Hospital, 332 N. Lauderdale, 38105-2794, Memphis, TN

    Yong-Mei Zhang, Ying-Jie Lu & Charles O. Rock

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  1. Yong-Mei Zhang
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  2. Ying-Jie Lu
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  3. Charles O. Rock
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Correspondence to Charles O. Rock.

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Zhang, YM., Lu, YJ. & Rock, C.O. The reductase steps of the type II fatty acid synthase as antimicrobial targets. Lipids 39, 1055–1060 (2004). https://doi.org/10.1007/s11745-004-1330-3

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  • DOI: https://doi.org/10.1007/s11745-004-1330-3

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