Bacterial fatty acid biosynthesis: targets for antibacterial drug discovery.

The increase in drug-resistant pathogenic bacteria has created an urgent demand for new antibiotics. Among the more attractive targets for the development of new antibacterial compounds are the enzymes of fatty acid biosynthesis. Although a number of potent inhibitors of microbial fatty acid biosynthesis have been discovered, few of these are clinically useful drugs. Several of these fatty acid biosynthesis inhibitors have potential as lead compounds in the development of new antibacterials. This review encompasses the known inhibitors and prospective targets for new antibacterials.

[1]  X. Yao,et al.  Comparison of the backbone dynamics of the apo‐ and holo‐carboxy‐terminal domain of the biotin carboxy1 carrier subunit of Escherichia coli acety1‐CoA carboxylase , 2008, Protein science : a publication of the Protein Society.

[2]  S. Abdel-Meguid,et al.  Molecular basis for triclosan activity involves a flipping loop in the active site , 2008, Protein science : a publication of the Protein Society.

[3]  R. Heath,et al.  Inhibition of β-Ketoacyl-Acyl Carrier Protein Synthases by Thiolactomycin and Cerulenin , 2001, The Journal of Biological Chemistry.

[4]  R. Slayden,et al.  Isoniazid affects multiple components of the type II fatty acid synthase system of Mycobacterium tuberculosis , 2000, Molecular microbiology.

[5]  N. Chirgadze,et al.  Crystal structure of Streptococcus pneumoniae acyl carrier protein synthase: an essential enzyme in bacterial fatty acid biosynthesis , 2000, The EMBO journal.

[6]  J. Cronan,et al.  Overproduction of Acetyl-CoA Carboxylase Activity Increases the Rate of Fatty Acid Biosynthesis in Escherichia coli * , 2000, The Journal of Biological Chemistry.

[7]  C. Rock,et al.  Identification and substrate specificity of beta -ketoacyl (acyl carrier protein) synthase III (mtFabH) from Mycobacterium tuberculosis. , 2000, The Journal of biological chemistry.

[8]  S. Gillespie,et al.  Comparison of fitness of two isolates of Mycobacterium tuberculosis, one of which had developed multi-drug resistance during the course of treatment. , 2000, The Journal of infection.

[9]  Charles O. Rock,et al.  erratum: A triclosan-resistant bacterial enzyme , 2000, Nature.

[10]  L. Bekker,et al.  Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[11]  K. Parris,et al.  Crystal structures of substrate binding to Bacillus subtilis holo-(acyl carrier protein) synthase reveal a novel trimeric arrangement of molecules resulting in three active sites. , 2000, Structure.

[12]  James C. Sacchettini,et al.  Inactivation of the inhA-Encoded Fatty Acid Synthase II (FASII) Enoyl-Acyl Carrier Protein Reductase Induces Accumulation of the FASI End Products and Cell Lysis of Mycobacterium smegmatis , 2000, Journal of bacteriology.

[13]  C. Townsend,et al.  Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. , 2000, Science.

[14]  S. Parikh,et al.  Inhibition of InhA, the enoyl reductase from Mycobacterium tuberculosis, by triclosan and isoniazid. , 2000, Biochemistry.

[15]  D Alland,et al.  Thiolactomycin and Related Analogues as Novel Anti-mycobacterial Agents Targeting KasA and KasB Condensing Enzymes inMycobacterium tuberculosis * , 2000, The Journal of Biological Chemistry.

[16]  Y. Lindqvist,et al.  Re-engineering ketoacyl synthase specificity. , 2000, Structure.

[17]  H M Holden,et al.  Movement of the Biotin Carboxylase B-domain as a Result of ATP Binding* , 2000, The Journal of Biological Chemistry.

[18]  P. T. Englund,et al.  Specialized fatty acid synthesis in African trypanosomes: myristate for GPI anchors. , 2000, Science.

[19]  J. Harwood,et al.  Novel inhibitors of the condensing enzymes of the type II fatty acid synthase of pea (Pisum sativum). , 2000, The Biochemical journal.

[20]  J. Rafferty,et al.  The X-ray structure of Brassica napus beta-keto acyl carrier protein reductase and its implications for substrate binding and catalysis. , 2000, Structure.

[21]  C. Townsend,et al.  Synthesis and antitumor activity of an inhibitor of fatty acid synthase , 2000 .

[22]  R. Heath,et al.  Inhibition of the Staphylococcus aureusNADPH-dependent Enoyl-Acyl Carrier Protein Reductase by Triclosan and Hexachlorophene* , 2000, The Journal of Biological Chemistry.

[23]  M. Jaquinod,et al.  Fatty Acid and Lipoic Acid Biosynthesis in Higher Plant Mitochondria* , 2000, The Journal of Biological Chemistry.

[24]  R. Slayden,et al.  Use of genomics and combinatorial chemistry in the development of new antimycobacterial drugs. , 2000, Biochemical pharmacology.

[25]  R. Heath,et al.  The 1.8 A crystal structure and active-site architecture of beta-ketoacyl-acyl carrier protein synthase III (FabH) from escherichia coli. , 2000, Structure.

[26]  C. Walsh,et al.  Holo-(Acyl Carrier Protein) Synthase and Phosphopantetheinyl Transfer in Escherichia coli * , 2000, The Journal of Biological Chemistry.

[27]  R. Strongin,et al.  Inhibition of biotin carboxylase by a reaction intermediate analog: implications for the kinetic mechanism. , 1999, Biochemical and biophysical research communications.

[28]  S. Abdel-Meguid,et al.  Crystal structure of beta-ketoacyl-acyl carrier protein synthase III. A key condensing enzyme in bacterial fatty acid biosynthesis. , 1999, The Journal of biological chemistry.

[29]  S. Larsen,et al.  CRYSTAL STRUCTURE OF BETA-KETOACYL-[ACYL CARRIER PROTEIN] SYNTHASE I FROM ESCHERICHIA COLI , 1999 .

[30]  P. Brown,et al.  Exploring drug-induced alterations in gene expression in Mycobacterium tuberculosis by microarray hybridization. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[31]  D W Rice,et al.  Inhibitor Binding Studies on Enoyl Reductase Reveal Conformational Changes Related to Substrate Recognition* , 1999, The Journal of Biological Chemistry.

[32]  S. Larsen,et al.  The X‐ray crystal structure of β‐ketoacyl [acyl carrier protein] synthase I , 1999 .

[33]  A. Chapman-Smith,et al.  The enzymatic biotinylation of proteins: a post-translational modification of exceptional specificity. , 1999, Trends in biochemical sciences.

[34]  I. Taylor,et al.  Kinetic and structural characteristics of the inhibition of enoyl (acyl carrier protein) reductase by triclosan. , 1999, Biochemistry.

[35]  I. H. Lim,et al.  Contribution of kasA Analysis to Detection of Isoniazid-Resistant Mycobacterium tuberculosisin Singapore , 1999, Antimicrobial Agents and Chemotherapy.

[36]  T. Schaeverbeke,et al.  In-vitro activity of grepafloxacin, a new fluoroquinolone, against mycoplasmas. , 1999, The Journal of antimicrobial chemotherapy.

[37]  T. Morris,et al.  Solution structures of apo and holo biotinyl domains from acetyl coenzyme A carboxylase of Escherichia coli determined by triple-resonance nuclear magnetic resonance spectroscopy. , 1999, Biochemistry.

[38]  R J Heath,et al.  Mechanism of Triclosan Inhibition of Bacterial Fatty Acid Synthesis* , 1999, The Journal of Biological Chemistry.

[39]  Antoni R. Slabas,et al.  Molecular basis of triclosan activity , 1999, Nature.

[40]  G. Schneider,et al.  Structure of the Complex between the Antibiotic Cerulenin and Its Target, β-Ketoacyl-Acyl Carrier Protein Synthase* , 1999, The Journal of Biological Chemistry.

[41]  P. McDermott,et al.  Genetic Evidence that InhA of Mycobacterium smegmatis Is a Target for Triclosan , 1999, Antimicrobial Agents and Chemotherapy.

[42]  D. Rice,et al.  Molecular genetic analysis of enoyl‐acyl carrier protein reductase inhibition by diazaborine , 1999, Molecular microbiology.

[43]  R. Heath,et al.  Broad Spectrum Antimicrobial Biocides Target the FabI Component of Fatty Acid Synthesis* , 1998, The Journal of Biological Chemistry.

[44]  Sonya S. Shin,et al.  The dilemma of MDR-TB in the global era. , 1998, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease.

[45]  D. Roos,et al.  Nuclear-encoded proteins target to the plastid in Toxoplasma gondii and Plasmodium falciparum. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[46]  S. Levy,et al.  Overexpression of marA, soxS, or acrAB produces resistance to triclosan in laboratory and clinical strains of Escherichia coli. , 1998, FEMS microbiology letters.

[47]  E. Schweizer,et al.  A Novel Phosphopantetheine:Protein Transferase Activating Yeast Mitochondrial Acyl Carrier Protein* , 1998, The Journal of Biological Chemistry.

[48]  S. Levy,et al.  Triclosan targets lipid synthesis , 1998, Nature.

[49]  J. Cronan,et al.  Transcriptional Analysis of Essential Genes of theEscherichia coli Fatty Acid Biosynthesis Gene Cluster by Functional Replacement with the Analogous Salmonella typhimurium Gene Cluster , 1998, Journal of bacteriology.

[50]  David A. Mead,et al.  Inhibition of a Mycobacterium tuberculosis β-Ketoacyl ACP synthase by isoniazid , 1998 .

[51]  T. Weisbrod,et al.  NADH Dehydrogenase Defects Confer Isoniazid Resistance and Conditional Lethality in Mycobacterium smegmatis , 1998, Journal of bacteriology.

[52]  J. Cronan,et al.  A Bacillus subtilis Gene Induced by Cold Shock Encodes a Membrane Phospholipid Desaturase , 1998, Journal of bacteriology.

[53]  G. Schneider,et al.  Crystal structure of β‐ketoacyl‐acyl carrier protein synthase II from E.coli reveals the molecular architecture of condensing enzymes , 1998, The EMBO journal.

[54]  J. Sacchettini,et al.  Modification of the NADH of the isoniazid target (InhA) from Mycobacterium tuberculosis. , 1998, Science.

[55]  J. Cronan,et al.  A New Metabolic Link , 1997, The Journal of Biological Chemistry.

[56]  S. Brody,et al.  Mitochondrial acyl carrier protein is involved in lipoic acid synthesis in Saccharomyces cerevisiae , 1997, FEBS letters.

[57]  J. Ohlrogge,et al.  Why do mitochondria synthesize fatty acids? Evidence for involvement in lipoic acid production. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[58]  Antoni R. Slabas,et al.  A Mechanism of Drug Action Revealed by Structural Studies of Enoyl Reductase , 1996, Science.

[59]  H. Bergler,et al.  The enoyl-[acyl-carrier-protein] reductase (FabI) of Escherichia coli, which catalyzes a key regulatory step in fatty acid biosynthesis, accepts NADH and NADPH as cofactors and is inhibited by palmitoyl-CoA. , 1996, European journal of biochemistry.

[60]  G. Besra,et al.  Antimycobacterial action of thiolactomycin: an inhibitor of fatty acid and mycolic acid synthesis , 1996, Antimicrobial agents and chemotherapy.

[61]  D. Sherman,et al.  Biochemical and genetic data suggest that InhA is not the primary target for activated isoniazid in Mycobacterium tuberculosis. , 1996, The Journal of infectious diseases.

[62]  R. Heath,et al.  Roles of the FabA and FabZ β-Hydroxyacyl-Acyl Carrier Protein Dehydratases in Escherichia coli Fatty Acid Biosynthesis* , 1996, The Journal of Biological Chemistry.

[63]  C. Rock,et al.  Escherichia coli as a model for the regulation of dissociable (type II) fatty acid biosynthesis. , 1996, Biochimica et biophysica acta.

[64]  J. L. Smith,et al.  Structure of a dehydratase-isomerase from the bacterial pathway for biosynthesis of unsaturated fatty acids: two catalytic activities in one active site. , 1996, Structure.

[65]  R. Heath,et al.  Regulation of Fatty Acid Elongation and Initiation by Acyl-Acyl Carrier Protein in Escherichia coli(*) , 1996, The Journal of Biological Chemistry.

[66]  W. Hendrickson,et al.  Structure of the biotinyl domain of acetyl-coenzyme A carboxylase determined by MAD phasing. , 1995, Structure.

[67]  R. Heath,et al.  Enoyl-Acyl Carrier Protein Reductase (fabI) Plays a Determinant Role in Completing Cycles of Fatty Acid Elongation in Escherichia coli(*) , 1995, The Journal of Biological Chemistry.

[68]  J. Cronan,et al.  The Unmodified (Apo) Form of Escherichia coli Acyl Carrier Protein Is a Potent Inhibitor of Cell Growth (*) , 1995, The Journal of Biological Chemistry.

[69]  J C Sacchettini,et al.  Enzymatic characterization of the target for isoniazid in Mycobacterium tuberculosis. , 1995, Biochemistry.

[70]  Z Dauter,et al.  The Escherichia coli Malonyl-CoA:Acyl Carrier Protein Transacylase at 1.5-Å Resolution. , 1995, The Journal of Biological Chemistry.

[71]  J. Cronan,et al.  The putative fabJ gene of Escherichia coli fatty acid synthesis is the fabF gene , 1995, Journal of bacteriology.

[72]  G. Bai,et al.  Molecular mechanisms of multiple drug resistance in clinical isolates of Mycobacterium tuberculosis. , 1995, The Journal of infectious diseases.

[73]  J. Sacchettini,et al.  Crystal structure and function of the isoniazid target of Mycobacterium tuberculosis , 1995, Science.

[74]  C. Raetz,et al.  An Escherichia coli gene (FabZ) encoding (3R)-hydroxymyristoyl acyl carrier protein dehydrase. Relation to fabA and suppression of mutations in lipid A biosynthesis. , 1994, The Journal of biological chemistry.

[75]  J. Olsen,et al.  The fabJ-encoded beta-ketoacyl-[acyl carrier protein] synthase IV from Escherichia coli is sensitive to cerulenin and specific for short-chain substrates. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[76]  P. Schultz,et al.  Mechanistic Studies of the Oxidation of Isoniazid by the Catalase Peroxidase from Mycobacterium tuberculosis , 1994 .

[77]  W. Jacobs,et al.  inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. , 1994, Science.

[78]  J. Rosner Susceptibilities of oxyR regulon mutants of Escherichia coli and Salmonella typhimurium to isoniazid , 1993, Antimicrobial Agents and Chemotherapy.

[79]  C. Rock,et al.  Thiolactomycin resistance in Escherichia coli is associated with the multidrug resistance efflux pump encoded by emrAB , 1993, Journal of bacteriology.

[80]  C. Rock,et al.  The dedB (usg) open reading frame of Escherichia coli encodes a subunit of acetyl-coenzyme A carboxylase , 1992, Journal of bacteriology.

[81]  J. Cronan,et al.  The genes encoding the two carboxyltransferase subunits of Escherichia coli acetyl-CoA carboxylase. , 1992, The Journal of biological chemistry.

[82]  S. Cole,et al.  The catalase—peroxidase gene and isoniazid resistance of Mycobacterium tuberculosis , 1992, Nature.

[83]  C. Rock,et al.  Isolation and characterization of the beta-ketoacyl-acyl carrier protein synthase III gene (fabH) from Escherichia coli K-12. , 1992, The Journal of biological chemistry.

[84]  J. Cronan,et al.  The gene encoding the biotin carboxylase subunit of Escherichia coli acetyl-CoA carboxylase. , 1992, The Journal of biological chemistry.

[85]  G. Högenauer,et al.  envM genes of Salmonella typhimurium and Escherichia coli , 1989, Journal of bacteriology.

[86]  J. Cronan The E. coli bio operon: Transcriptional repression by an essential protein modification enzyme , 1989, Cell.

[87]  Y. Iitaka,et al.  Structure of thiolactomycin. , 1989, Acta crystallographica. Section C, Crystal structure communications.

[88]  C. Rock,et al.  Acetoacetyl-acyl carrier protein synthase. A target for the antibiotic thiolactomycin. , 1989, The Journal of biological chemistry.

[89]  M. Yamada,et al.  Effect of thiolactomycin on the individual enzymes of the fatty acid synthase system in Escherichia coli. , 1986, Journal of biochemistry.

[90]  A. Kawaguchi,et al.  Inhibition of fatty acid synthesis by the antibiotic thiolactomycin. , 1984, The Journal of antibiotics.

[91]  M. Polacco,et al.  β-Hydroxydecanoyl thio ester dehydrase does not catalyze a rate-limiting step in Escherichia coli unsaturated fatty acid synthesis , 1983 .

[92]  H. Okazaki,et al.  Mechanism of action of the antibiotic thiolactomycin inhibition of fatty acid synthesis of Escherichia coli. , 1983, Biochemical and biophysical research communications.

[93]  J. Cronan,et al.  Genetic and Biochemical Analyses of Escherichia coli Mutants Altered in the Temperature-Dependent Regulation of Membrane Lipid Composition , 1983, Journal of bacteriology.

[94]  S. Ōmura,et al.  Thiotetromycin, a new antibiotic. Taxonomy, production, isolation, and physicochemical and biological properties. , 1983, The Journal of antibiotics.

[95]  Y. Harada,et al.  Thiolactomycin, a new antibiotic. IV. Biological properties and chemotherapeutic activity in mice. , 1982, The Journal of antibiotics.

[96]  H. Sasaki,et al.  Thiolactomycin, a new antibiotic. II. Structure elucidation. , 1982, The Journal of antibiotics.

[97]  H. Okazaki,et al.  Thiolactomycin, a new antibiotic. III. In vitro antibacterial activity. , 1982, The Journal of antibiotics.

[98]  H. Okazaki,et al.  THIOLACTOMYCIN, A NEW ANTIBIOTIC , 1982 .

[99]  M. Polacco,et al.  A mutant of Escherichia coli conditionally defective in the synthesis of holo-[acyl carrier protein]. , 1981, The Journal of biological chemistry.

[100]  J. Cronan,et al.  Structural, enzymatic, and genetic studies of beta-ketoacyl-acyl carrier protein synthases I and II of Escherichia coli. , 1980, The Journal of biological chemistry.

[101]  J. Cronan,et al.  Beta-ketoacyl-acyl carrier protein synthase II of Escherichia coli. Evidence for function in the thermal regulation of fatty acid synthesis. , 1980, The Journal of biological chemistry.

[102]  L. Ingram,et al.  Inhibition of unsaturated fatty acid synthesis in escherichia coli by the antibiotic cerulenin. , 1978, Biochemistry.

[103]  S. Ōmura The antibiotic cerulenin, a novel tool for biochemistry as an inhibitor of fatty acid synthesis. , 1976, Bacteriological reviews.

[104]  S Omura,et al.  Inhibition of fatty acid synthesis by the antibiotic cerulenin. Specific inactivation of beta-ketoacyl-acyl carrier protein synthetase. , 1973, Biochimica et biophysica acta.

[105]  S. Ōmura,et al.  Inhibition of fatty acid synthetases by the antibiotic cerulenin. , 1972, Biochemical and biophysical research communications.

[106]  S. Nomura,et al.  The action mechanism of cerulenin. I. Effect of cerulenin on sterol and fatty acid biosynthesis in yeast. , 1972, Journal of biochemistry.

[107]  K. Bloch,et al.  Mycobacterium phlei Fatty Acid Synthetase—A Bacterial Multienzyme Complex , 1969, Nature.

[108]  K. Bloch,et al.  Unsaturated fatty acids in microorganisms. , 1962, The Journal of biological chemistry.

[109]  H. Goldfine,et al.  On the origin of unsaturated fatty acids in clostridia. , 1961, The Journal of biological chemistry.

[110]  E. J. Thomas,et al.  Asymmetric synthesis of 5,5-disubstituted thiotetronic acids using anallyl xanthate to dithiocarbonate rearrangement: total synthesis of(5S)-thiolactomycin with revision of the absolute configurationof the natural , 1997 .

[111]  D van Soolingen,et al.  Characterization of the catalase-peroxidase gene (katG) and inhA locus in isoniazid-resistant and -susceptible strains of Mycobacterium tuberculosis by automated DNA sequencing: restricted array of mutations associated with drug resistance. , 1996, The Journal of infectious diseases.

[112]  M. Marahiel,et al.  A new enzyme superfamily - the phosphopantetheinyl transferases. , 1996, Chemistry & biology.

[113]  S. Iwasaki,et al.  Effect of side-chain structure on inhibition of yeast fatty-acid synthase by cerulenin analogues. , 1993, European journal of biochemistry.

[114]  I. V. Still,et al.  Synthesis of 2-butenolide and tetronic acid analogs of thiolactomycin , 1989 .

[115]  S. Kauppinen,et al.  β-ketoacyl-ACP synthase I of Escherichia coli: Nucleotide sequence of thefabB gene and identification of the cerulenin binding residue , 1988, Carlsberg research communications.

[116]  David J. Williams,et al.  An asymmetric synthesis of thiotetronic acids using chirality transfer via an allyl xanthate-to-dithiocarbonate rearrangement. X-Ray crystal structure of (5R)-2,5-dihydro-4-hydroxy-5-methyl-3-phenyl-5-prop-1′-enyl-2-oxothiophene , 1987 .

[117]  O. Sebek,et al.  Isolation and structure of antibiotic U-68,204, a new thiolactone. , 1986, The Journal of antibiotics.

[118]  P. Sedmera,et al.  Two thiolactones from Streptomyces Tü 2476. , 1985, The Journal of antibiotics.

[119]  J. Salvino,et al.  Total ssynthesis of (±) thiolactomycin☆ , 1984 .

[120]  Y. Shizuri,et al.  Isolation and structure of citroethiolactone, a novel metabolite of Penicillium citreo-viride B. , 1983 .

[121]  M. Lane,et al.  Biotin carboxylase component of acetyl-CoA carboxylase from Escherichia coli. , 1975, Methods in enzymology.

[122]  M. Lane,et al.  Carboxyltransferase component of acetyl-CoA carboxylase from Escherichia coli. , 1975, Methods in enzymology.

[123]  K. Bloch 15 β-Hydroxydecanoyl Thioester Dehydrase , 1971 .