Inhibitors of fatty acid synthesis as antimicrobial chemotherapeutics

被引:163
作者
Heath, RJ
White, SW
Rock, CO
机构
[1] St Jude Childrens Res Hosp, Dept Infect Dis, Prot Sci Div, Memphis, TN 38105 USA
[2] St Jude Childrens Res Hosp, Dept Biol Struct, Memphis, TN 38105 USA
[3] Univ Tennessee, Ctr Hlth Sci, Dept Mol Sci, Memphis, TN 38163 USA
关键词
D O I
10.1007/s00253-001-0918-z
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Fatty acid biosynthesis is an emerging target for the development of novel antibacterial chemotherapeutics. The dissociated bacterial system is substantially different from the large, multifunctional protein of mammals, and many possibilities exist for type-selective drugs. Several compounds, both synthetic and natural, target bacterial fatty acid synthesis. Three compounds target the FabI enoyl-ACP reductase step; isoniazid, a clinically used antituberculosis drug, triclosan, a widely used consumer antimicrobial, and diazaborines. In addition, cerulenin and thiolactomycin, two fungal products, inhibit the FabH, FabB and FabF condensation enzymes. Finally, the synthetic reaction intermediates BP1 and decynoyl-N-acetyl cysteamine inhibit the acetyl-CoA carboxylase and dehydratase isomerase steps, respectively. The mechanisms of action of these compounds, as well as the potential development of new drugs targeted against this pathway, are discussed.
引用
收藏
页码:695 / 703
页数:9
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共 72 条
[51]  
OMURA S, 1967, J ANTIBIOT, V20, P349
[52]   Inhibition of InhA, the enoyl reductase from Mycobacterium tuberculosis, by triclosan and isoniazid [J].
Parikh, SL ;
Xiao, GP ;
Tonge, PJ .
BIOCHEMISTRY, 2000, 39 (26) :7645-7650
[53]   In vitro activity of a novel antimycobacterial compound, N-octanesulfonylacetamide, and its effects on lipid and mycolic acid synthesis [J].
Parrish, NM ;
Houston, T ;
Jones, PB ;
Townsend, C ;
Dick, JD .
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2001, 45 (04) :1143-1150
[54]   Structure of β-ketoacyl-[acyl carrier protein] reductase from Escherichia coli:: Negative cooperativity and its structural basis [J].
Price, AC ;
Zhang, YM ;
Rock, CO ;
White, SW .
BIOCHEMISTRY, 2001, 40 (43) :12772-12781
[55]   Inhibition of β-ketoacyl-acyl carrier protein syntheses by thiolactomycin and cerulenin -: Structure and mechanism [J].
Price, AC ;
Choi, KH ;
Heath, RJ ;
Li, ZM ;
White, SW ;
Rock, CO .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (09) :6551-6559
[56]   ENZYMATIC CHARACTERIZATION OF THE TARGET FOR ISONIAZID IN MYCOBACTERIUM-TUBERCULOSIS [J].
QUEMARD, A ;
SACCHETTINI, JC ;
DESSEN, A ;
VILCHEZE, C ;
BITTMAN, R ;
JACOBS, WR ;
BLANCHARD, JS .
BIOCHEMISTRY, 1995, 34 (26) :8235-8241
[57]  
REGOS J, 1974, ZBL BAKT-INT J MED M, V226, P390
[58]   Crystal structure of the Mycobacterium tuberculosis enoyl-ACP reductase, InhA, in complex with NAD+ and a C16 fatty acyl substrate [J].
Rozwarski, DA ;
Vilchèze, C ;
Sugantino, M ;
Bittman, R ;
Sacchettini, JC .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (22) :15582-15589
[59]   Modification of the NADH of the isoniazid target (InhA) from Mycobacterium tuberculosis [J].
Rozwarski, DA ;
Grant, GA ;
Barton, DHR ;
Jacobs, WR ;
Sacchettini, JC .
SCIENCE, 1998, 279 (5347) :98-102
[60]   Response of Bacillus subtilis to cerulenin and acquisition of resistance [J].
Schujman, GE ;
Choi, KH ;
Altabe, S ;
Rock, CO ;
de Mendoza, D .
JOURNAL OF BACTERIOLOGY, 2001, 183 (10) :3032-3040