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Mechanism of Triclosan Inhibition of Bacterial Fatty Acid Synthesis

Published on Apr 16, 1999in Journal of Biological Chemistry
· DOI :10.1074/jbc.274.16.11110
Richard J. Heath34
Estimated H-index: 34
(St. Jude Children's Research Hospital),
J. Ronald Rubin3
Estimated H-index: 3
(St. Jude Children's Research Hospital)
+ 3 AuthorsCharles O. Rock26
Estimated H-index: 26
(St. Jude Children's Research Hospital)
Cite
Abstract
Abstract Triclosan is a broad-spectrum antibacterial agent that inhibits bacterial fatty acid synthesis at the enoyl-acyl carrier protein reductase (FabI) step. Resistance to triclosan inEscherichia coli is acquired through a missense mutation in the fabI gene that leads to the expression of FabI[G93V]. The specific activity and substrate affinities of FabI[G93V] are similar to FabI. Two different binding assays establish that triclosan dramatically increases the affinity of FabI for NAD+. In contrast, triclosan does not increase the binding of NAD+to FabI[G93V]. The x-ray crystal structure of the FabI-NAD+-triclosan complex confirms that hydrogen bonds and hydrophobic interactions between triclosan and both the protein and the NAD+ cofactor contribute to the formation of a stable ternary complex, with the drug binding at the enoyl substrate site. These data show that the formation of a noncovalent “bi-substrate” complex accounts for the effectiveness of triclosan as a FabI inhibitor and illustrates that mutations in the FabI active site that interfere with the formation of a stable FabI-NAD+-triclosan ternary complex acquire resistance to the drug.
  • References (24)
  • Citations (347)
Cite
References24
Newest
Published on Jan 1, 1991
Dennis E. Vance70
Estimated H-index: 70
,
Jean E. Vance53
Estimated H-index: 53
1. Physical Properties and Functional Roles of Lipids in Membranes (Pieter R. Cullis and Michael J. Hope). 2. Lipid Metabolism in Procaryotes (Suzanne Jackowski, John E. Cronan, Jr. and Charles O. Rock). 3. Oxidation of Fatty Acids (Horst Schulz) 4. Fatty Acid Synthesis in Eucaryotes (Alan G. Goodridge). 5. Fatty Acid Desaturation and Chain Elongation in Eucaryotes (Harold W. Cook). 6. Metabolism of Triacylglycerols (David N. Brindley) 7. Phospholipid Metabolism and Cell Signaling in Eucaryotes ...
Published on Nov 13, 1998in Journal of Biological Chemistry
Richard J. Heath34
Estimated H-index: 34
(St. Jude Children's Research Hospital),
Yuen-Tsu Yu1
Estimated H-index: 1
(St. Jude Children's Research Hospital)
+ 2 AuthorsCharles O. Rock26
Estimated H-index: 26
(St. Jude Children's Research Hospital)
Abstract The broad spectrum antibacterial properties of 2-hydroxydiphenyl ethers have been appreciated for decades, and their use in consumer products is rapidly increasing. We identify the enoyl-acyl carrier protein reductase (fabI) component of the type II fatty acid synthase system as the specific cellular target for these antibacterials. Biologically active 2-hydroxydiphenyl ethers effectively inhibit fatty acid synthesis in vivo and FabI activity in vitro. Resistant mechanisms include up-re...
Published on Aug 1, 1998in Nature43.07
Laura M. McMurry24
Estimated H-index: 24
(Tufts University),
Margret Oethinger11
Estimated H-index: 11
(Tufts University),
Stuart B. Levy77
Estimated H-index: 77
(Tufts University)
Triclosan is a broad-spectrum antibacterial and antifungal agent1,2, which acts by previously undetermined mechanisms, that is used in products such as antiseptic soaps, toothpastes, fabrics and plastics. Here we show that triclosan blocks lipid synthesis in Escherichia coli, and that mutations in, or overexpression of, the gene fabI (which encodes enoyl reductase, involved in fatty acid synthesis) prevents this blockage. This is, to our knowledge, the first evidence that triclosan acts on a spe...
Published on Jul 1, 1998in Journal of Bacteriology3.23
Yan Zhang3
Estimated H-index: 3
,
John E. Cronan73
Estimated H-index: 73
(UIUC: University of Illinois at Urbana–Champaign)
The genes encoding several key fatty acid biosynthetic enzymes (called the fab cluster) are clustered in the order plsX-fabH-fabD-fabG-acpP-fabF at min 24 of the Escherichia coli chromosome. A difficulty in analysis of the fab cluster by the polar allele duplication approach (Y. Zhang and J. E. Cronan, Jr., J. Bacteriol. 178:3614–3620, 1996) is that several of these genes are essential for the growth of E. coli. We overcame this complication by use of the fab gene cluster of Salmonella typhimuri...
Published on Jan 2, 1998in Science41.04
Denise A. Rozwarski4
Estimated H-index: 4
,
Gregory A. Grant37
Estimated H-index: 37
+ 2 AuthorsJames C. Sacchettini82
Estimated H-index: 82
The preferred antitubercular drug isoniazid specifically targets a long-chain enoyl-acyl carrier protein reductase (InhA), an enzyme essential for mycolic acid biosynthesis in Mycobacterium tuberculosis . Despite the widespread use of this drug for more than 40 years, its precise mode of action has remained obscure. Data from x-ray crystallography and mass spectrometry reveal that the mechanism of isoniazid action against InhA is covalent attachment of the activated form of the drug to the nicot...
Published on Dec 20, 1996in Science41.04
Clair Baldock27
Estimated H-index: 27
(University of Sheffield),
John B. Rafferty27
Estimated H-index: 27
(University of Sheffield)
+ 5 AuthorsDavid W. Rice51
Estimated H-index: 51
(University of Sheffield)
Enoyl reductase (ENR), an enzyme involved in fatty acid biosynthesis, is the target for antibacterial diazaborines and the front-line antituberculosis drug isoniazid. Analysis of the structures of complexes of Escherichia coli ENR with nicotinamide adenine dinucleotide and either thienodiazaborine or benzodiazaborine revealed the formation of a covalent bond between the 2′ hydroxyl of the nicotinamide ribose and a boron atom in the drugs to generate a tight, noncovalently bound bisubstrate analo...
Published on Dec 15, 1996in FEBS Journal4.74
Helmut Bergler18
Estimated H-index: 18
(University of Graz),
Sandra Fuchsbichler5
Estimated H-index: 5
(University of Graz)
+ 1 AuthorsFriederike Turnowsky15
Estimated H-index: 15
(University of Graz)
Reduction of enoyl -acyl-carrier-protein (ACP) substrates by enoyl-ACP reductase is a key regulatory step in fatty acid elongation of Escherichia coli. Two enoyl-ACP reductase activities have been described in E. coli, one specific for NADH, the other for NADPH as cofactor. Because of their distinct enzymatic properties, these activities were ascribed to two different proteins. The NADH-dependent enoyl-ACP reductase of E. coli has previously been identified as the FabI protein, which is the targ...
Published on Nov 1, 1996in Journal of Biological Chemistry
Richard J. Heath34
Estimated H-index: 34
(St. Jude Children's Research Hospital),
Charles O. Rock C O59
Estimated H-index: 59
(UTHSC: University of Tennessee Health Science Center)
Abstract There are two genes, fabA and fabZ, encoding β-hydroxyacyl-acyl carrier protein (ACP) dehydratases that function in the dissociated, type II fatty acid synthase system of Escherichia coli. We have investigated their roles in fatty acid synthesis by purifying the two proteins and reconstituting cycles of fatty acid synthesis in vitro using five other purified proteins. FabA and FabZ exhibited broad, overlapping chain length specificities. The FabZ dehydratase efficiently catalyzed the de...
Published on Jul 1, 1996in Biochimica et Biophysica Acta3.79
Charles O. Rock26
Estimated H-index: 26
(UT: University of Tennessee),
John E. Cronan73
Estimated H-index: 73
(UIUC: University of Illinois at Urbana–Champaign)
Published on Jun 1, 1996in American Journal of Infection Control1.97
H.N. Bhargava1
Estimated H-index: 1
(MCPHS University),
Patricia A. Leonard1
Estimated H-index: 1
(MCPHS University)
Abstract Triclosan (2,4,4′-trichloro-2′-hydroxydiphenyl ether) is a nonionic, broad spectrum, antimicrobial agent that, because of its favorable safety profile, has been incorporated into a variety of many personal care products, including deodorant soaps, underarm deodorants, shower gels, and health care personnel handwashes. Triclosan exhibits a moderate degree of substantivity to the skin, and, in many products, it imparts a remnant antimicrobial effect. Although direct contact with the mater...
Cited By347
Newest
Published on Mar 21, 2019in Scientific Reports4.01
Sannah Jensen Zoffmann5
Estimated H-index: 5
(Hoffmann-La Roche),
Maarten Vercruysse (Hoffmann-La Roche)+ 16 AuthorsMichael Prummer16
Estimated H-index: 16
(Swiss Institute of Bioinformatics)
Identification of novel antibiotics remains a major challenge for drug discovery. The present study explores use of phenotypic readouts beyond classical antibacterial growth inhibition adopting a combined multiparametric high content screening and genomic approach. Deployment of the semi-automated bacterial phenotypic fingerprint (BPF) profiling platform in conjunction with a machine learning-powered dataset analysis, effectively allowed us to narrow down, compare and predict compound mode of ac...
Published on 2019in The Journal of Antibiotics2.45
Małgorzata Ligowska-Marzęta1
Estimated H-index: 1
,
Viktoria Hancock + 1 AuthorsFrank Møller Aarestrup79
Estimated H-index: 79
Biocides are chemical compounds widely used for sterilization and disinfection. The aim of this study was to examine whether exposure to subinhibitory biocide concentrations influenced transcriptional expression of genes that could improve a pathogen’s drug resistance or fitness. We used DNA microarrays to investigate the transcriptome of the uropathogenic Escherichia coli strain CFT073 in response to prolonged exposure to subinhibitory concentrations of four biocides: benzalkonium chloride, chl...
Published on Jul 6, 2019in Journal of Applied Phycology2.63
Said Abu-Ghosh5
Estimated H-index: 5
(BIU: Bar-Ilan University),
Brit Ronen + 3 AuthorsDavid Iluz14
Estimated H-index: 14
(BIU: Bar-Ilan University)
Because of their high lipid content, microalgae are regarded as a potentially competitive source for biofuels. However, one of the main biotechnological challenges in algae-based biofuels is that cell division is arrested under conditions which promote lipid accumulation, resulting in reduced overall lipid yield. In this study, sethoxydim-resistant mutants of the promising thermotolerant green microalga Micractinium sp., which has a relatively fast growth rate and tolerance to outdoor high tempe...
Published on Jun 28, 2019in bioRxiv
Yue Xing (UIUC: University of Illinois at Urbana–Champaign), Shuaiqi Wu (UIUC: University of Illinois at Urbana–Champaign), Yujie Men (UIUC: University of Illinois at Urbana–Champaign)
Antibiotic resistance is one of the most challenging issues in public health. Antibiotic resistance can be selected by antibiotics at sub-inhibitory concentrations, the concentrations typically occurring in natural and engineered environments. Meanwhile, many other emerging organic contaminants such as pesticides are frequently co-occurring with antibiotics in agriculture-related environments and municipal wastewater treatment plants. To investigate the effects of the co-existing, non-antibiotic...
Published on Jun 1, 2019in Ecotoxicology and Environmental Safety4.53
Debarati Paul15
Estimated H-index: 15
(Amity Institute of Biotechnology),
Ranadhir Chakraborty12
Estimated H-index: 12
(University of North Bengal),
Santi M. Mandal23
Estimated H-index: 23
(IIT-KGP: Indian Institute of Technology Kharagpur)
Abstract Health-care chemicals are used worldwide as important components of different industries as consumer products, food industry, animal husbandry and agribusiness. There are innumerable reports on the effect of these chemicals (biocides) impacting the development of cross to co-resistance in pathogenic bacteria. However, reports are limited on the concurrent use of agricides (pesticides, herbicides, fungicides and insecticides) which influence the microbial activities in soils and contribu...
Published on Jun 1, 2019in Chemosphere5.11
Kai Sun1
Estimated H-index: 1
(AAU: Anhui Agricultural University),
Shunyao Li1
Estimated H-index: 1
(NAU: Nanjing Agricultural University)
+ 4 AuthorsGang Chu (AAU: Anhui Agricultural University)
Abstract Laccase-mediated humification processes (L-MHPs) can be used to polymerize and transform phenolic pollutants in water. However, the mechanism on Cu 2+ impacts the self-polymerization of multi-purpose antimicrobial agent triclosan during L-MHPs is less understood. Here, the influence of divalent metal ions (DMIs) on Trametes versicolor laccase activity was investigated. Particularly, the performance of Cu 2+ -assisted laccase in polymerizing and transforming triclosan was systematically ...
Published on May 6, 2019in bioRxiv
Jeff Maltas2
Estimated H-index: 2
(UM: University of Michigan),
Brian Krasnick (UM: University of Michigan), Kevin Wood8
Estimated H-index: 8
(UM: University of Michigan)
Bacterial resistance to one antibiotic is frequently accompanied by cross-resistance to other drugs. Similarly, non-antibiotic selective forces, from biocides to osmotic stress, have been shown to decrease antibiotic susceptibility, often the result of shared, non-specific resistance mechanisms. On the other hand, evolved resistance to particular antibiotics may also be associated with increased sensitivity to other drugs, high-lighting evolutionary constraints that could form the basis for nove...
Published on Apr 15, 2019in Critical Reviews in Microbiology5.70
Ellis C. O’Neill7
Estimated H-index: 7
(University of Oxford),
Michelle Schorn7
Estimated H-index: 7
(UCSD: University of California, San Diego)
+ 1 AuthorsNatalie Millán-Aguiñaga (UABC: Autonomous University of Baja California)
AbstractIntense competition between microbes in the environment has directed the evolution of antibiotic production in bacteria. Humans have harnessed these natural molecules for medicinal purposes...
Published on May 1, 2019in Plant Physiology6.30
Kjell De Vriese1
Estimated H-index: 1
(UGent: Ghent University),
Ellie Himschoot4
Estimated H-index: 4
(UGent: Ghent University)
+ 8 AuthorsTom Beeckman65
Estimated H-index: 65
(UGent: Ghent University)
Many signal perception mechanisms are connected to Ca 2+ -based second messenger signaling to modulate specific cellular responses. The well-characterized plant hormone auxin elicits a very rapid Ca 2+ signal. However, the cellular targets of auxin-induced Ca 2+ are largely unknown. Here, we screened a biologically annotated chemical library for inhibitors of auxin-induced Ca 2+ entry in plant cell suspensions to better understand the molecular mechanism of auxin-induced Ca 2+ and to explore the...