Review

Inhibitors of fatty acid synthesis in prokaryotes and eukaryotes as anti-infective, anticancer and anti-obesity drugs

Jingxin Wang

Ryan Hudson

Herman O Sintim

Jingxin Wang

Department of Chemistry & Biochemistry, University of Maryland, College Park, MD 20742, USA

Search for more papers by this author

Ryan Hudson

Theravance, Inc. 901 Gateway Boulevard, South San Francisco, CA 94080, USA

Search for more papers by this author

Herman O Sintim

* Author for correspondence

Department of Chemistry & Biochemistry, University of Maryland, College Park, MD 20742, USA.

Search for more papers by this author

Email the corresponding author at hsintim@umd.edu

Published Online:18 Jun 2012https://doi.org/10.4155/fmc.12.62

View article

Abstract

There is a large range of diseases, such diabetes and cancer, which are connected to abnormal fatty acid metabolism in human cells. Therefore, inhibitors of human fatty acid synthase have great potential to manage or treat these diseases. In prokaryotes, fatty acid synthesis is important for signaling, as well as providing starting materials for the synthesis of phospholipids, which are required for the formation of the cell membrane. Recently, there has been renewed interest in the development of new molecules that target bacterial fatty acid synthases for the treatment of bacterial diseases. In this review, we look at the differences and similarities between fatty acid synthesis in humans and bacteria and highlight various small molecules that have been shown to inhibit either the mammalian or bacterial fatty acid synthase or both.

Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

References

1 Menendez JA, Lupu R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat. Rev. Cancer7(10),763–777 (2007).▪▪ Reviews fatty acid synthesis in cancerous cells.
Medline CASGoogle Scholar
2 Kuhajda FP. Fatty acid synthase and cancer: new application of an old pathway. Cancer Res.66(12),5977–5980 (2006).
Medline CASGoogle Scholar
3 Zhang YM, White SW, Rock CO. Inhibiting bacterial fatty acid synthesis. J. Biol. Chem.281(26),17541–17544 (2006).
Medline CASGoogle Scholar
4 Smith S, Tsai SC. The type I fatty acid and polyketide synthases: a tale of two megasynthases. Nat. Prod. Rep.24(5),1041–1072 (2007).
Medline CASGoogle Scholar
5 Wright HT, Reynolds KA. Antibacterial targets in fatty acid biosynthesis. Curr. Opin. Microbiol.10(5),447–453 (2007).
Medline CASGoogle Scholar
6 Campbell JW, Cronan JE. Bacterial fatty acid biosynthesis: targets for antibacterial drug discovery. Annu. Rev. Microbiol.55,305–332 (2001).
Medline CASGoogle Scholar
7 Rada PV, Hoebel BG. Supraadditive effect of d-fenfluramine plus phentermine on extracellular acetylcholine in the nucleus accumbens: possible mechanism for inhibition of excessive feeding and drug abuse. Pharmacol. Biochem. Behav.65(3),369–373 (2000).
Medline CASGoogle Scholar
8 Hainer V, Kabrnova K, Aldhoon B, Kunesova M, Wagenknecht M. Serotonin and norepinephrine reuptake inhibition and eating behavior. Ann. NY Acad. Sci.1083,252–269 (2006).
Medline CASGoogle Scholar
9 Kang JG, Park CY. Anti-obesity drugs: a review about their effects and safety. Diabetes Metab. J.36(1),13–25 (2012).
MedlineGoogle Scholar
10 Finer N. Sibutramine: its mode of action and efficacy. Int. J. Obes. Relat. Metab. Disord.26(Suppl. 4),S29–S33 (2002).
Medline CASGoogle Scholar
11 Fong TM, Heymsfield SB. Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions. Int. J. Obes., 33(9),947–955 (2009).
CASGoogle Scholar
12 Hochuli E, Kupfer E, Maurer R, Meister W, Mercadal Y, Schmidt K. Lipstatin, an inhibitor of pancreatic lipase, produced by Streptomyces toxytricini. II. Chemistry and structure elucidation. J. Antibiot.40(8),1086–1091 (1987).
Medline CASGoogle Scholar
13 Zhi J, Melia AT, Eggers H, Joly R, Patel IH. Review of limited systemic absorption of orlistat, a lipase inhibitor, in healthy human volunteers. J. Clin. Pharmacol.35(11),1103–1108 (1995).
Medline CASGoogle Scholar
14 Harrison-Woolrych M, Ashton J, Herbison P. Fatal and non-fatal cardiovascular events in a general population prescribed sibutramine in New Zealand: a prospective cohort study. Drug Saf.33(7),605–613 (2010).
MedlineGoogle Scholar
15 Mitchell PB, Morris MJ. Depression and anxiety with rimonabant. Lancet370(9600),1671–1672 (2007).
MedlineGoogle Scholar
16 Nakazato M, Murakami N, Date Y et al. A role for ghrelin in the central regulation of feeding. Nature409(6817),194–198 (2001).
Medline CASGoogle Scholar
17 Lage R, Vazquez MJ, Varela L et al. Ghrelin effects on neuropeptides in the rat hypothalamus depend on fatty acid metabolism actions on BSX but not on gender. FASEB J.24(8),2670–2679 (2010).
Medline CASGoogle Scholar
18 Barnett BP, Hwang Y, Taylor MS et al. Glucose and weight control in mice with a designed ghrelin O-acyltransferase inhibitor. Science330(6011),1689–1692 (2010).
Medline CASGoogle Scholar
19 Mera P, Bentebibel A, Lopez-Vinas E et al. C75 is converted to C75-CoA in the hypothalamus, where it inhibits carnitine palmitoyltransferase 1 and decreases food intake and body weight. Biochem. Pharmacol.77(6),1084–1095 (2009).
Medline CASGoogle Scholar
20 Petersen KF, Oral EA, Dufour S et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J. Clin. Invest.109(10),1345–1350 (2002).
Medline CASGoogle Scholar
21 Kim YD, Park KG, Lee YS et al. Metformin inhibits hepatic gluconeogenesis through AMP-activated protein kinase-dependent regulation of the orphan nuclear receptor SHP. Diabetes57(2),306–314 (2008).
Medline CASGoogle Scholar
22 Donath MY, Ehses JA, Maedler K et al. Mechanisms of beta-cell death in Type 2 diabetes. Diabetes54(Suppl. 2),S108–S113 (2005).
Medline CASGoogle Scholar
23 Luzi L, Pozza G. Glibenclamide: an old drug with a novel mechanism of action? Acta Diabetol.34(4),239–244 (1997).
Medline CASGoogle Scholar
24 Samulitis BK, Goda T, Lee SM, Koldovsky O. Inhibitory mechanism of acarbose and 1-deoxynojirimycin derivatives on carbohydrases in rat small intestine. Drugs Exp. Clin. Res., 13(8),517–524 (1987).
Medline CASGoogle Scholar
25 Bolen S, Feldman L, Vassy J et al. Systematic review: comparative effectiveness and safety of oral medications for Type 2 diabetes mellitus. Ann. Intern. Med.147(6),386–399 (2007).
MedlineGoogle Scholar
26 Nomura S, Sakamaki S, Hongu M et al. Discovery of canagliflozin, a novel C-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of Type 2 diabetes mellitus. J. Med. Chem.53(17),6355–6360 (2010).
Medline CASGoogle Scholar
27 Zhang L, Keung W, Samokhvalov V, Wang W, Lopaschuk GD. Role of fatty acid uptake and fatty acid beta-oxidation in mediating insulin resistance in heart and skeletal muscle. Biochim. Biophys. Acta1801(1),1–22 (2010).
Medline CASGoogle Scholar
28 Espinosa E, Zamora P, Feliu J, Gonzalez Baron M. Classification of anticancer drugs – a new system based on therapeutic targets. Cancer Treat. Rev.29(6),515–523 (2003).
Medline CASGoogle Scholar
29 Rajagopalan PT, Zhang Z, McCourt L, Dwyer M, Benkovic SJ, Hammes GG. Interaction of dihydrofolate reductase with methotrexate: ensemble and single-molecule kinetics. Proc. Natl Acad. Sci. USA99(21),13481–13486 (2002).
Medline CASGoogle Scholar
30 Waters TR, Swann PF. Cytotoxic mechanism of 6-thioguanine: hMutSalpha, the human mismatch binding heterodimer, binds to DNA containing S6-methylthioguanine. Biochemistry36(9),2501–2506 (1997).
Medline CASGoogle Scholar
31 Jamieson ER, Lippard SJ. Structure, recognition, and processing of cisplatin-DNA adducts. Chem. Rev.99(9),2467–2498 (1999).
Medline CASGoogle Scholar
32 Fuertes MA, Castilla J, Alonso C, Perez JM. Cisplatin biochemical mechanism of action: from cytotoxicity to induction of cell death through interconnections between apoptotic and necrotic pathways. Curr. Med. Chem.10(3),257–266 (2003).
Medline CASGoogle Scholar
33 Burden DA, Osheroff N. Mechanism of action of eukaryotic topoisomerase II and drugs targeted to the enzyme. Biochim. Biophys. Acta1400(1–3),139–154 (1998).
Medline CASGoogle Scholar
34 Desta Z, Ward BA, Soukhova NV, Flockhart DA. Comprehensive evaluation of tamoxifen sequential biotransformation by the human cytochrome P450 system in vitro: prominent roles for CYP3A and CYP2D6. J. Pharmacol. Exp. Ther.310(3),1062–1075 (2004).
Medline CASGoogle Scholar
35 Iorns E, Lord CJ, Ashworth A. Parallel RNAi and compound screens identify the PDK1 pathway as a target for tamoxifen sensitization. Biochem. J.417(1),361–370 (2009).
Medline CASGoogle Scholar
36 Horwitz SB. Taxol (paclitaxel): mechanisms of action. Ann. Oncol.5(Suppl. 6),S3–S6 (1994).
MedlineGoogle Scholar
37 Boehm T, Folkman J, Browder T, O’Reilly MS. Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance. Nature390(6658),404–407 (1997).
Medline CASGoogle Scholar
38 Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol. Cancer Ther.7(10),3129–3140 (2008).
Medline CASGoogle Scholar
39 Chen KF, Chen HL, Tai WT et al. Activation of phosphatidylinositol 3-kinase/Akt signaling pathway mediates acquired resistance to sorafenib in hepatocellular carcinoma cells. J. Pharmacol. Exp. Ther.337(1),155–161 (2011).
Medline CASGoogle Scholar
40 Ozols RF, Bundy BN, Greer BE et al. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J. Clin. Oncol.21(17),3194–3200 (2003).
Medline CASGoogle Scholar
41 Gottesman MM. Mechanisms of cancer drug resistance. Annu. Rev. Med.53,615–627 (2002).
Medline CASGoogle Scholar
42 Paik S, Shak S, Tang G et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N. Engl. J. Med.351(27),2817–2826 (2004).
Medline CASGoogle Scholar
43 Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat. Rev. Drug Discov.4(12),988–1004 (2005).
Medline CASGoogle Scholar
44 Koppenol WH, Bounds PL, Dang CV. Otto Warburg’s contributions to current concepts of cancer metabolism. Nat. Rev. Cancer11(5),325–337 (2011).
Medline CASGoogle Scholar
45 Menendez JA, Vellon L, Mehmi I et al. Inhibition of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells. Proc. Natl Acad. Sci. USA101(29),10715–10720 (2004).
Medline CASGoogle Scholar
46 Liu H, Liu JY, Wu X, Zhang JT. Biochemistry, molecular biology, and pharmacology of fatty acid synthase, an emerging therapeutic target and diagnosis/prognosis marker. Int. J. Biochem. Mol. Biol.1(1),69–89 (2010).
Medline CASGoogle Scholar
47 Howden BP, Ward PB, Charles PG et al. Treatment outcomes for serious infections caused by methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility. Clin. Infect. Dis.38(4),521–528 (2004).
Medline CASGoogle Scholar
48 McDermott PF, Zhao S, Wagner DD, Simjee S, Walker RD, White DG. The food safety perspective of antibiotic resistance. Anim. Biotechnol.13(1),71–84 (2002).
Medline CASGoogle Scholar
49 White DG, Zhao S, Sudler R et al. The isolation of antibiotic-resistant salmonella from retail ground meats. N. Engl. J. Med.345(16),1147–1154 (2001).
Medline CASGoogle Scholar
50 Raviglione MC, Smith IM. XDR tuberculosis – implications for global public health. N. Engl. J. Med.356(7),656–659 (2007).
Medline CASGoogle Scholar
51 Grundmann H, Aires-de-Sousa M, Boyce J, Tiemersma E. Emergence and resurgence of meticillin-resistant Staphylococcus aureus as a public-health threat. Lancet368(9538),874–885 (2006).
MedlineGoogle Scholar
52 Yong D, Toleman MA, Giske CG et al. Characterization of a new metallo-beta-lactamase gene, bla(NDM-1), and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India. Antimicrob. Agents Chemother.53(12),5046–5054 (2009).
Medline CASGoogle Scholar
53 Poirel L, Lagrutta E, Taylor P, Pham J, Nordmann P. Emergence of metallo-beta-lactamase NDM-1-producing multidrug-resistant Escherichia coli in Australia. Antimicrob. Agents Chemother.54(11),4914–4916 (2010).
Medline CASGoogle Scholar
54 Mochon AB, Garner OB, Hindler JA et al. New Delhi metallo-beta-lactamase (NDM-1)-producing Klebsiella pneumoniae: case report and laboratory detection strategies. J. Clin. Microbiol.49(4),1667–1670 (2011).
Medline CASGoogle Scholar
55 Dye C, Williams BG, Espinal MA, Raviglione MC. Erasing the world’s slow stain: strategies to beat multidrug-resistant tuberculosis. Science295(5562),2042–2046 (2002).
Medline CASGoogle Scholar
56 Shah NS, Wright A, Bai GH et al. Worldwide emergence of extensively drug-resistant tuberculosis. Emerg. Infect. Dis.13(3),380–387 (2007).
Medline CASGoogle Scholar
57 Huycke MM, Sahm DF, Gilmore MS. Multiple-drug resistant enterococci: the nature of the problem and an agenda for the future. Emerg. Infect. Dis.4(2),239–249 (1998).
Medline CASGoogle Scholar
58 Kollef MH. Gram-negative bacterial resistance: evolving patterns and treatment paradigms. Clin. Infect. Dis.40(S2),S85–S88 (2005).
MedlineGoogle Scholar
59 Livermore DM. Multiple mechanisms of antimicrobial resistance in Pseudomonas aeruginosa: our worst nightmare? Clin. Infect. Dis.34(5),634–640 (2002).
Medline CASGoogle Scholar
60 Li XZ, Ma D, Livermore DM, Nikaido H. Role of efflux pump(s) in intrinsic resistance of Pseudomonas aeruginosa: active efflux as a contributing factor to beta-lactam resistance. Antimicrob. Agents Chemother.38(8),1742–1752 (1994).
Medline CASGoogle Scholar
61 Masuda N, Sakagawa E, Ohya S, Gotoh N, Tsujimoto H, Nishino T. Contribution of the MexX-MexY-oprM efflux system to intrinsic resistance in Pseudomonas aeruginosa. Antimicrob. Agents Chemother.44(9),2242–2246 (2000).
Medline CASGoogle Scholar
62 Li XZ, Livermore DM, Nikaido H. Role of efflux pump(s) in intrinsic resistance of Pseudomonas aeruginosa: resistance to tetracycline, chloramphenicol, and norfloxacin. Antimicrob. Agents Chemother.38(8),1732–1741 (1994).
Medline CASGoogle Scholar
63 Schweizer HP. Intrinsic resistance to inhibitors of fatty acid biosynthesis in Pseudomonas aeruginosa is due to efflux: application of a novel technique for generation of unmarked chromosomal mutations for the study of efflux systems. Antimicrob. Agents Chemother.42(2),394–398 (1998).
Medline CASGoogle Scholar
64 D’Costa VM, King CE, Kalan L et al. Antibiotic resistance is ancient. Nature477(7365),457–461 (2011).
MedlineGoogle Scholar
65 Kumarasamy KK, Toleman MA, Walsh TR et al. Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study. Lancet Infect. Dis.10(9),597–602 (2010).
Medline CASGoogle Scholar
66 Poirel L, Lagrutta E, Taylor P, Pham J, Nordmann P. Emergence of metallo-beta-lactamase NDM-1-producing multidrug-resistant Escherichia coli in Australia. Antimicrob. Agents Chemother.54(11),4914–4916 (2010).
Medline CASGoogle Scholar
67 Poirel L, Revathi G, Bernabeu S, Nordmann P. Detection of NDM-1-producing Klebsiella pneumoniae in Kenya. Antimicrob. Agents Chemother.55(2),934–936 (2011).
Medline CASGoogle Scholar
68 Mulvey MR, Grant JM, Plewes K, Roscoe D, Boyd DA. New Delhi metallo-beta-lactamase in Klebsiella pneumoniae and Escherichia coli, Canada. Emerg. Infect. Dis.17(1),103–106 (2011).
Medline CASGoogle Scholar
69 WHO. The Global Plan to Stop TB, 2011–2015. WHO, Geneva, Switzerland (2010).
Google Scholar
70 Mediterranean E. The Global Tuberculosis Epidemic; Nov. 2010 – Fact Sheet; No. 7883–7802. Kaiser Family Foundation, Menlo Park, CA, USA (2010).
Google Scholar
71 Novak R, Henriques B, Charpentier E, Normark S, Tuomanen E. Emergence of vancomycin tolerance in Streptococcus pneumoniae. Nature399(6736),590–593 (1999).
Medline CASGoogle Scholar
72 Chiosis G, Boneca IG. Selective cleavage of D-Ala-D-Lac by small molecules: re-sensitizing resistant bacteria to vancomycin. Science293(5534),1484–1487 (2001).
Medline CASGoogle Scholar
73 Uttley AH, Collins CH, Naidoo J, George RC. Vancomycin-resistant enterococci. Lancet1(8575–8576),57–58 (1988).
Medline CASGoogle Scholar
74 Moellering RC, Linden PK, Reinhardt J, Blumberg EA, Bompart F, Talbot GH. The efficacy and safety of quinupristin/dalfopristin for the treatment of infections caused by vancomycin-resistant Enterococcus faecium. J. Antimicrob. Chemother.44(2),251–261 (1999).
Medline CASGoogle Scholar
75 Stevens DL, Herr D, Lampiris H, Hunt JL, Batts DH, Hafkin B. Linezolid versus vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections. Clin. Infect. Dis.34(11),1481–1490 (2002).
Medline CASGoogle Scholar
76 Tally FP, Zeckel M, Wasilewski MM et al. Daptomycin: a novel agent for Gram-positive infections. Expert Opin. Investig. Drugs8(8),1223–1238 (1999).
Medline CASGoogle Scholar
77 Schmitz FJ, Sadurski R, Stattfeld A, Kray A, Verhoef J, Fluit AC. Cross-resistance analyses and molecular typing of Staphylococcus aureus and Streptococcus spp. isolates resistant to quinupristin/dalfopristin. J. Antimicrob. Chemother.44(6),847–849 (1999).
Medline CASGoogle Scholar
78 Lewis JS 2nd, Owens A, Cadena J, Sabol K, Patterson JE, Jorgensen JH. Emergence of daptomycin resistance in Enterococcus faecium during daptomycin therapy. Antimicrob. Agents Chemother.49(4),1664–1665 (2005).
MedlineGoogle Scholar
79 Tsiodras S, Gold HS, Sakoulas G et al. Linezolid resistance in a clinical isolate of Staphylococcus aureus. Lancet358(9277),207–208 (2001).
Medline CASGoogle Scholar
80 Singer SJ, Nicolson GL. The fluid mosaic model of the structure of cell membranes. Science175(23),720–731 (1972).
Medline CASGoogle Scholar
81 Raetz CR, Whitfield C. Lipopolysaccharide endotoxins. Annu. Rev. Biochem.71,635–700 (2002).
Medline CASGoogle Scholar
82 Brennan PJ, Nikaido H. The envelope of mycobacteria. Annu. Rev. Biochem.64,29–63 (1995).
Medline CASGoogle Scholar
83 Minnikin DE, Kremer L, Dover LG, Besra GS. The methyl-branched fortifications of Mycobacterium tuberculosis. Chem. Biol.9,545–553 (2002).
Medline CASGoogle Scholar
84 Witkowski A, Ghosal A, Joshi AK, Witkowska HE, Asturias FJ, Smith S. Head-to-head coiled arrangement of the subunits of the animal fatty acid synthase. Chem. Biol.11(12),1667–1676 (2004).
Medline CASGoogle Scholar
85 Asturias FJ, Chadick JZ, Cheung IK et al. Structure and molecular organization of mammalian fatty acid synthase. Nat. Struct. Mol. Biol.12(3),225–232 (2005).
Medline CASGoogle Scholar
86 Wakil SJ, Porter JW, Gibson DM. Studies on the mechanism of fatty acid synthesis. 1. Preparation and purification of an enzyme system for reconstruction of fatty acid synthesis. J. Biochim. Biophys. Acta24(3),453–461 (1957).
Medline CASGoogle Scholar
87 Hiltunen JK, Schonauer MS, Autio KJ, Mittelmeier TM, Kastaniotis AJ, Dieckmann CL. Mitochondrial fatty acid synthesis type II: more than just fatty acids. J. Biol. Chem.284(14),9011–9015 (2009).
Medline CASGoogle Scholar
88 Kridel SJ, Lowther WT, Pemble CW. Fatty acid synthase inhibitors: new directions for oncology. Expert Opin. Inv. Drug.16(11),1817–1829 (2007).
Medline CASGoogle Scholar
89 Lomakin IB, Xiong Y, Steitz TA. The crystal structure of yeast fatty acid synthase, a cellular machine with eight active sites working together. Cell129(2),319–332 (2007).
MedlineGoogle Scholar
90 Maier T, Jenni S, Ban N. Architecture of mammalian fatty acid synthase at 4.5 Å resolution. Science311(5765),1258–1262 (2006).
Medline CASGoogle Scholar
91 Maier T, Leibundgut M, Boehringer D, Ban N. Structure and function of eukaryotic fatty acid synthases. Q. Rev. Biophys.43(3),373–422 (2010).
Medline CASGoogle Scholar
92 Smith S, Witkowski A, Joshi AK. Structural and functional organization of the animal fatty acid synthase. Prog. Lipid Res.42(4),289–317 (2003).
Medline CASGoogle Scholar
93 Abu-Elheiga L, Brinkley WR, Zhong L, Chirala SS, Woldegiorgis G, Wakil SJ. The subcellular localization of acetyl-CoA carboxylase 2. Proc. Natl Acad. Sci. USA97(4),1444–1449 (2000).▪ Provides insight on human ACC2 function and localization.
Medline CASGoogle Scholar
94 Yu LP, Kim YS, Tong L. Mechanism for the inhibition of the carboxyltransferase domain of acetyl-coenzyme A carboxylase by pinoxaden. Proc. Natl Acad. Sci. USA107(51),22072–22077 (2010).
Medline CASGoogle Scholar
95 Lee CK, Cheong HK, Ryu KS et al. Biotinoyl domain of human acetyl-CoA carboxylase: structural insights into the carboxyl transfer mechanism. Proteins Struct. Funct. Bioinf.72(2),613–624 (2008).
Medline CASGoogle Scholar
96 Wakil SJ. Fatty acid synthase, a proficient multifunctional enzyme. Biochemistry28(11),4523–4530 (1989).
Medline CASGoogle Scholar
97 Wakil SJ, Stoops JK, Joshi VC. Fatty acid synthesis and its regulation. Annu. Rev. Biochem.52,537–579 (1983).
Medline CASGoogle Scholar
98 Chen Z, Leskinen H, Liimatta E et al. Myocardial overexpression of Mecr, a gene of mitochondrial FAS II leads to cardiac dysfunction in mouse. PLoS ONE4(5),e5589 (2009).
MedlineGoogle Scholar
99 Schneider R, Massow M, Lisowsky T, Weiss H. Different respiratory-defective phenotypes of Neurospora crassa and Saccharomyces cerevisiae after inactivation of the gene encoding the mitochondrial acyl carrier protein. Curr. Genet.29(1),10–17 (1995).
Medline CASGoogle Scholar
100 Witkowski A, Joshi AK, Smith S. Coupling of the de novo fatty acid biosynthesis and lipoylation pathways in mammalian mitochondria. J. Biol. Chem.282(19),14178–14185 (2007).
Medline CASGoogle Scholar
101 Guler JL, Kriegova E, Smith TK, Lukes J, Englund PT. Mitochondrial fatty acid synthesis is required for normal mitochondrial morphology and function in Trypanosoma brucei. Mol. Microbiol.67(5),1125–1142 (2008).
Medline CASGoogle Scholar
102 Morita YS, Paul KS, Englund PT. Specialized fatty acid synthesis in African trypanosomes: myristate for GPI anchors. Science288(5463),140–143 (2000).
Medline CASGoogle Scholar
103 Yi X, Maeda N. Endogenous production of lipoic acid is essential for mouse development. Mol. Cell. Biol.25(18),8387–8392 (2005).
Medline CASGoogle Scholar
104 Parsons JB, Rock CO. Is bacterial fatty acid synthesis a valid target for antibacterial drug discovery? Curr. Opin. Microbiol.14(5),544–549 (2011).▪▪ Summarizes the recent debate on whether fatty acid synthesis is a suitable target for develeping antibiotics and provides an excellent perspective on this issue.
Medline CASGoogle Scholar
105 Lu YJ, Zhang YM, Grimes KD, Qi J, Lee RE, Rock CO. Acyl-phosphates initiate membrane phospholipid synthesis in Gram-positive pathogens. Mol. Cell23(5),765–772 (2006).
Medline CASGoogle Scholar
106 Smith S, Witkowski A, Joshi AK. Structural and functional organization of the animal fatty acid synthase. Prog. Lipid Res.42(4),289–317 (2003).
Medline CASGoogle Scholar
107 Lu YJ, Zhang YM, Rock CO. Product diversity and regulation of type II fatty acid synthases. Biochem. Cell Biol.82(1),145–155 (2004).
Medline CASGoogle Scholar
108 Kaneda T. Fatty acids of the genus Bacillus: an example of branched-chain preference. Bacteriol. Rev.41(2),391–418 (1977).
Medline CASGoogle Scholar
109 Cronan JE, Waldrop GL. Multi-subunit acetyl-CoA carboxylases. Prog. Lipid Res.41,407 (2002).
Medline CASGoogle Scholar
110 Lambalot RH, Walsh CT. Cloning, overproduction, and characterization of the Escherichia coli holo-acyl carrier protein synthase. J. Biol. Chem.270(42),24658 (1995).
Medline CASGoogle Scholar
111 Kuhajda FP, Jenner K, Wood FD et al. Fatty acid synthesis: a potential selective target for antineoplastic therapy. Proc. Natl Acad. Sci. USA91(14),6379–6383 (1994).
Medline CASGoogle Scholar
112 White SW, Zheng J, Zhang YM, Rock CO. The structural biology of type II fatty acid biosynthesis. Annu. Rev. Biochem.74,791–831 (2005).
Medline CASGoogle Scholar
113 Qiu X, Janson CA, Konstantinidis AK et al. Crystal structure of beta-ketoacyl-acyl carrier protein synthase III. A key condensing enzyme in bacterial fatty acid biosynthesis. J. Biol. Chem.274(51),36465–36471 (1999).
Medline CASGoogle Scholar
114 Haapalainen AM, Merilainen G, Wierenga RK. The thiolase superfamily: condensing enzymes with diverse reaction specificities. Trends Biochem. Sci.31(1),64–71 (2006).
Medline CASGoogle Scholar
115 Schaefer AL, Val DL, Hanzelka BL, John E, Cronan JE Jr, Greenberg EP. Generation of cell-to-cell signals in quorum sensing: acyl homoserine lactone synthase activity of a purified Vibrio fischeri LuxI protein. Proc. Natl Acad. Sci. USA93,9505 (1996).
Medline CASGoogle Scholar
116 Raetz CRH, Garrett TA, Reynolds CM et al. Kdo₂-lipid A of Escherichia coli, a defined endotoxin that activates macrophages via TLR-4. J. Lipid Res.47,1097 (2006).
Medline CASGoogle Scholar
117 Harwood HJ Jr. Treating the metabolic syndrome: acetyl-CoA carboxylase inhibition. Expert Opin. Ther. Targets9(2),267–281 (2005).
Medline CASGoogle Scholar
118 Zhang H, Tweel B, Li J, Tong L. Crystal structure of the carboxyltransferase domain of acetyl-coenzyme A carboxylase in complex with CP-640186. Structure12(9),1683–1691 (2004).
Medline CASGoogle Scholar
119 Corbett JW, Freeman-Cook KD, Elliott R et al. Discovery of small molecule isozyme non-specific inhibitors of mammalian acetyl-CoA carboxylase 1 and 2. Bioorg. Med. Chem. Lett.20(7),2383–2388 (2010).
Medline CASGoogle Scholar
120 Harwood HJ Jr, Petras SF, Shelly LD et al. Isozyme-nonselective N-substituted bipiperidylcarboxamide acetyl-CoA carboxylase inhibitors reduce tissue malonyl-CoA concentrations, inhibit fatty acid synthesis, and increase fatty acid oxidation in cultured cells and in experimental animals. J. Biol. Chem.278(39),37099–37111 (2003).
Medline CASGoogle Scholar
121 Schupp T, Toupet C, Cluzel B et al. A Sorangium cellulosum (myxobacterium) gene cluster for the biosynthesis of the macrolide antibiotic soraphen A: cloning, characterization, and homology to polyketide synthase genes from actinomycetes. J. Bacteriol.177(13),3673–3679 (1995).
Medline CASGoogle Scholar
122 Vahlensieck HF, Pridzun L, Reichenbach H, Hinnen A. Identification of the yeast ACC1 gene product (acetyl-CoA carboxylase) as the target of the polyketide fungicide soraphen A. Curr. Genet.25(2),95–100 (1994).
Medline CASGoogle Scholar
123 Beckers A, Organe S, Timmermans L et al. Chemical inhibition of acetyl-CoA carboxylase induces growth arrest and cytotoxicity selectively in cancer cells. Cancer Res.67(17),8180–8187 (2007).
Medline CASGoogle Scholar
124 Fredenhagen A, Tamura SY, Kenny PTM, Komura H, Naya Y, Nakanishi K. Andrimid, a new peptide antibiotic produced by an intracellular bacterial symbiont isolated from a brown planthopper. J. Am. Chem. Soc.109(14),4409 (1987).
CASGoogle Scholar
125 Davies SG, Dixon DJ. Asymmetric syntheses of moiramide B and andrimid. J. Chem. Soc. Perkin Trans.1,2635–2644 (1998).
Google Scholar
126 Freiberg C, Brunner NA, Schiffer G et al. Identification and characterization of the first class of potent bacterial acetyl-CoA carboxylase inhibitors with antibacterial activity. J. Biol. Chem.279(25),26066 (2004).
Medline CASGoogle Scholar
127 Lin T-W, Melgar MM, Kurth D et al. Structure-based inhibitor design of AccD5, an essential acyl-CoA carboxylase carboxyltransferase domain of Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA103,3072–3077 (2006).
Medline CASGoogle Scholar
128 Lin T-W, Nguyen T, Kurth D et al. Structure-based inhibitor design of AccD5/AccD6, essential carboxyltransferases of Mycobacterium tuberculosis. FASEB J.33,839–834 (2008).
Google Scholar
129 Kurth DG, Gago GM, Iglesia Adl et al. Accase 6 is the essential acetyl-CoA carboxylase involved in fatty acid and mycolic acid biosynthesis in mycobacteria. Microbiology155,2664 (2009).
Medline CASGoogle Scholar
130 Levert KL, Waldrop GL, Stephens JM. A biotin analog inhibits acetyl-CoA carboxylase activity and adipogenesis. J. Biol. Chem.277(19),16347–16350 (2002).
Medline CASGoogle Scholar
131 Levert KL, Waldrop GL. A bisubstrate analog inhibitor of the carboxyltransferase component of acetyl-CoA carboxylase. Biochem. Biophys. Res. Commun.291(5),1213–1217 (2002).
Medline CASGoogle Scholar
132 Chu M, Mierzwa R, Xu L et al. Structure elucidation of Sch 538415, a novel acyl carrier protein synthase inhibitor from a microorganism. Bioorg. Med. Chem. Lett.13,3827 (2003).
Medline CASGoogle Scholar
133 Gilbert AM, Kirisits M, Toy P et al. Anthranilate 4H-oxazol-5-ones: novel small molecule antibacterial acyl carrier protein synthase (AcpS) inhibitors. Bioorg. Med. Chem. Lett.14,37–41 (2004).
Medline CASGoogle Scholar
134 Joseph-McCarthy D, Parris K, Huang A et al. Use of structure-based drug design approaches to obtain novel anthranilic acid acyl carrier protein synthase inhibitors. J. Med. Chem.48,7960–7069 (2005).
Medline CASGoogle Scholar
135 Liu W, Han C, Hua L, Chen K, Shen X, Jiang H. Characterization and inhibitor discovery of one novel malonyl-CoA: acyl carrier protein transacylase (MCAT) from Helicobacter pylori. FEBS Lett.580(2),697–702 (2006).
Medline CASGoogle Scholar
136 Price AC, Rock CO, White SW. The 1.3-angstrom-resolution crystal structure of beta-ketoacyl-acyl carrier protein synthase II from Streptococcus pneumoniae. J. Bacteriol.185(14),4136–4143 (2003).
Medline CASGoogle Scholar
137 Oishi H, Noto T, Sasaki H et al. Thiolactomycin, a new antibiotic. I. Taxonomy of the producing organism, fermentation and biological properties. J. Antibiot. (Tokyo)35,391–395 (1982).
Medline CASGoogle Scholar
138 Campbell JW, Cronan JE. Bacterial fatty acid biosynthesis: targets for antibacterial drug discovery. Annu. Rev. Microbiol.55,305–332 (2001).
Medline CASGoogle Scholar
139 Machutta CA, Bommineni GR, Luckner SR et al. Slow onset inhibition of bacterial beta-ketoacyl-acyl carrier protein synthases by thiolactomycin. J. Biol. Chem.285(9),6161–6169 (2009).
MedlineGoogle Scholar
140 Matsumae A, Nomura S, Hata T. Studies on cerulenin. IV. Biological characteristics of cerulenin. J. Antibiot. (Tokyo)17,1 (1964).
Medline CASGoogle Scholar
141 Li XC, Joshi AS, ElSohly HN et al. Fatty acid synthase inhibitors from plants: isolation, structure elucidation, and SAR studies. J. Nat. Prod.65(12),1909–1914 (2002).
Medline CASGoogle Scholar
142 Price AC, Choi K-H, Heath RJ, Li Z, White SW, Rock CO. Inhibition of b-ketoacyl-acyl carrier protein synthases by thiolactomycin and cerulenin. Structure and mechanism. J. Biol. Chem.276(9),6551–6555 (2001).
Medline CASGoogle Scholar
143 Moche M, Schneider G, Edwards P, Dehesh K, Lindqvist Y. Structure of the complex between the antibiotic cerulenin and its target, β-ketoacyl-acyl carrier protein synthase. J. Biol. Chem.274(10),6031–6034 (1999).
Medline CASGoogle Scholar
144 Morisaki N, Funabashi H, Shimazawa R et al. Effect of side-chain structure on inhibition of yeast fatty-acid synthase by cerulenin analogues. Eur. J. Biochem.211,111–115 (1993).
Medline CASGoogle Scholar
145 Kuhajda FP, Pizer ES, Li JN, Mani NS, Frehywot GL, Townsend CA. Synthesis and antitumor activity of an inhibitor of fatty acid synthase. Proc. Natl Acad. Sci. USA97(7),3450–3454 (2000).
Medline CASGoogle Scholar
146 Thupari JN, Kim EK, Moran TH, Ronnett GV, Kuhajda FP. Chronic C75 treatment of diet-induced obese mice increases fat oxidation and reduces food intake to reduce adipose mass. Am. J. Physiol. Endocrinol. Metab.287(1),E97–E104 (2004).
Medline CASGoogle Scholar
147 Wang X, Lin J, Chen Y et al. Novel fatty acid synthase (FAS) inhibitors: design, synthesis, biological evaluation, and molecular docking studies. Bioorg. Med. Chem.17(5),1898–1904 (2009).
Medline CASGoogle Scholar
148 Wang X, Zhao G, Chen Y et al. 1-oxo-3-substitute-isothiochroman-4-carboxylic acid compounds: synthesis and biological activities of FAS inhibition. Bioorg. Med. Chem. Lett.19(3),770–772 (2009).
Medline CASGoogle Scholar
149 Liu X, Shi Y, Giranda VL, Luo Y. Inhibition of the phosphatidylinositol 3-kinase/Akt pathway sensitizes MDA-MB468 human breast cancer cells to cerulenin-induced apoptosis. Mol. Cancer Ther.5(3),494–501 (2006).
Medline CASGoogle Scholar
150 Cha SH, Hu Z, Chohnan S, Lane MD. Inhibition of hypothalamic fatty acid synthase triggers rapid activation of fatty acid oxidation in skeletal muscle. Proc. Natl Acad. Sci. USA102(41),14557–14562 (2005).
Medline CASGoogle Scholar
151 Tu Y, Thupari JN, Kim EK et al. C75 alters central and peripheral gene expression to reduce food intake and increase energy expenditure. Endocrinology146(1),486–493 (2005).
Medline CASGoogle Scholar
152 Zhang YM, Hurlbert J, White SW, Rock CO. Roles of the active site water, histidine 303, and phenylalanine 396 in the catalytic mechanism of the elongation condensing enzyme of Streptococcus pneumoniae. J. Biol. Chem.281(25),17390–17399 (2006).
Medline CASGoogle Scholar
153 Miyakawa S, Suzuki K, Noto T, Harada Y, Okazaki H. Thiolactomycin, a new antibitoic. IV. Biological properties and chemotherapeutic activity in mice. J. Antibiot. (Tokyo)35,411–419 (1982).
Medline CASGoogle Scholar
154 Omura S, Iwai Y, Nakagawa A et al. Thiotetromycin, a new antibiotic. Taxonomy, production, isolation, and physicochemical and biological properties. J. Antibiot. (Tokyo)36,109–114 (1983).
Medline CASGoogle Scholar
155 McFadden JM, Medghalchi SM, Thupari JN et al. Application of a flexible synthesis of (5R)-thiolactomycin to develop new inhibitors of type I fatty acid synthase. J. Med. Chem.48(4),946–961 (2005).
Medline CASGoogle Scholar
156 Rivkin A, Kim YR, Goulet MT et al. 3-aryl-4-hydroxyquinolin-2(1H)-one derivatives as type I fatty acid synthase inhibitors. Bioorg. Med. Chem. Lett.16(17),4620–4623 (2006).
Medline CASGoogle Scholar
157 Zeng XF, Li WW, Fan HJ et al. Discovery of novel fatty acid synthase (FAS) inhibitors based on the structure of ketoaceyl synthase (KS) domain. Bioorg. Med. Chem. Lett.21(16),4742–4744 (2011).
Medline CASGoogle Scholar
158 Kodali S, Galgoci A, Young K et al. Determination of selectivity and efficacy of fatty acid synthesis inhibitors. J. Biol. Chem.280,1669–1669 (2005).
Medline CASGoogle Scholar
159 Young K, Jayasuriya H, Ondeyka JG et al. Discovery of FabH/FabF inhibitors from natural products. Antimicrob. Agents Chemother.50(2),519 (2006).
Medline CASGoogle Scholar
160 Wang J, Soisson SM, Young K et al. Platensimycin is a selective FabF inhibitor with potent antibiotic properties. Nature441(7091),358–361 (2006).▪▪ Discovery of one of the most potent inhibitors of fatty acid synthases (FAS).
Medline CASGoogle Scholar
161 Wang J, Kodali S, Lee SH et al. Discovery of platencin, a dual FabF and FabH inhibitor with in vivo antibiotic properties. Proc. Natl Acad. Sci. USA104(18),7612–7616 (2007).
Medline CASGoogle Scholar
162 Wang J, Lee V, Sintim HO. Efforts towards the identification of simpler platensimycin analogues – the total synthesis of oxazinidinyl platensimycin. Chem. Eur. J.15,2747 (2009).
Medline CASGoogle Scholar
163 Shen HC, Ding FX, Singh SB et al. Synthesis and biological evaluation of platensimycin analogs. Bioorg. Med. Chem. Lett.19(6),1623–1627 (2009).
Medline CASGoogle Scholar
164 Nicolaou KC, Stepan AF, Lister T et al. Design, synthesis, and biological evaluation of platensimycin analogues with varying degrees of molecular complexity. J. Am. Chem. Soc.130(39),13110–13119 (2008).
Medline CASGoogle Scholar
165 Walsh CT, Haynes SW, Ames BD. Aminobenzoates as building blocks for natural product assembly lines. Nat. Prod. Rep.29,37–59 (2012).
Medline CASGoogle Scholar
166 Wu M, Singh SB, Wang J et al. Antidiabetic and antisteatotic effects of the selective fatty acid synthase (FAS) inhibitor platensimycin in mouse models of diabetes. Proc. Natl Acad. Sci. USA108(13),5378–5383 (2011).▪▪ Demonstrates that the potent FAS inhibitor, platensimycin, has antidiabetes properties.
Medline CASGoogle Scholar
167 Burcelin R, Serino M, Chabo C, Blasco-Baque V, Amar J. Gut microbiota and diabetes: from pathogenesis to therapeutic perspective. Acta Diabetol.48(4),257–273 (2011).
MedlineGoogle Scholar
168 He X, Reynolds KA. Purification, characterization, and identification of novel inhibitors of the b-ketoacyl-acyl carrier protein synthase III (FabH) from Staphylococcus aureus. Antimicrob. Agents Chemother.46(5),1310 (2002).
Medline CASGoogle Scholar
169 Nie Z, Perretta C, Lu J et al. Structure-based design, synthesis, and study of potent inhibitors of b-ketoacyl-acyl carrier protein synthase III as potential antimicrobial agents. J. Med. Chem.48,1596–1609 (2005).
Medline CASGoogle Scholar
170 Lee JY, Jeong KW, Lee JU, Kang DI, Kim Y. Novel E. coli beta-ketoacyl-acyl carrier protein synthase III inhibitors as targeted antibiotics. Bioorg. Med. Chem.17(4),1506–1513 (2009).
Medline CASGoogle Scholar
171 Lee JY, Jeong KW, Shin S, Lee JU, Kim Y. Antimicrobial natural products as beta-ketoacyl-acyl carrier protein synthase III inhibitors. Bioorg. Med. Chem.17(15),5408–5413 (2009).
Medline CASGoogle Scholar
172 Patel MP, Liu WS, West J, Tew D, Meek TD, Thrall SH. Kinetic and chemical mechanisms of the fabG-encoded Streptococcus pneumoniae beta-ketoacyl-ACP reductase. Biochemistry44(50),16753–16765 (2005).
Medline CASGoogle Scholar
173 Price AC, Zhang YM, Rock CO, White SW. Cofactor-induced conformational rearrangements establish a catalytically competent active site and a proton relay conduit in FabG. Structure12(3),417–428 (2004).
Medline CASGoogle Scholar
174 Silva RG, de Carvalho LP, Blanchard JS, Santos DS, Basso LA. Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein (ACP) reductase: kinetic and chemical mechanisms. Biochemistry45(43),13064–13073 (2006).
Medline CASGoogle Scholar
175 Wang X, Tian WX. Green tea epigallocatechin gallate: a natural inhibitor of fatty-acid synthase. Biochem. Biophys. Res. Commun.288(5),1200–1206 (2001).
Medline CASGoogle Scholar
176 Wang X, Song KS, Guo QX, Tian WX. The galloyl moiety of green tea catechins is the critical structural feature to inhibit fatty-acid synthase. Biochem. Pharmacol.66(10),2039–2047 (2003).
Medline CASGoogle Scholar
177 Zhang Y-M, Rock CO. Evaluation of epigallocatechin gallate and related plant polyphenols as inhibitors of the FabG and FabI reductases of bacterial type II fatty-acid synthase. J. Biol. Chem.279(30),30994–31001 (2004).
Medline CASGoogle Scholar
178 Yang L, Liu Y, Sternberg C, Molin S. Evaluation of enoyl-acyl carrier protein reductase inhibitors as pseudomonas aeruginosa quorum-quenching reagents. Molecules15(2),780–792 (2010).
Medline CASGoogle Scholar
179 Kumar G, Parasuraman P, Sharma SK et al. Discovery of a rhodanine class of compounds as inhibitors of Plasmodium falciparum enoyl-acyl carrier protein reductase. J. Med. Chem.50(11),2665–2675 (2007).
Medline CASGoogle Scholar
180 Wang H, Cronan JE. Functional replacement of the FabA and FabB proteins of Escherichia coli fatty acid synthesis by Enterococcus faecalis FabZ and FabF homologues. J. Biol. Chem.279(33),34489 (2004).
Medline CASGoogle Scholar
181 Kass LR. The antibacterial activity of 3-decynoyl-N-acetylcysteamine: inhibition in vivo of b-hydroxydecanoyl thioester dehydrase. J. Biol. Chem.243(12),3223–3228 (1968).
Medline CASGoogle Scholar
182 Morisaki M, Bloch K. Inhibition of β-hydroxydecanoyl thioester dehydrase by some allenic acids and their thioesters. Bioorg. Chem.1,188–193 (1971).
CASGoogle Scholar
183 Sharma SK, Kapoor M, Ramya TNC et al. Identification, characterization, and inhibition of Plasmodium falciparum b-hydroxyacyl-acyl carrier protein dehydratase (FabZ). J. Biol. Chem.278(46),45661–45671 (2003).
Medline CASGoogle Scholar
184 Lu H, Tonge PJ. Mechanism and inhibition of the FabV enoyl-ACP reductase from Burkholderia mallei. Biochemistry49(6),1281–1289 (2010).
Medline CASGoogle Scholar
185 Heath RJ, Rock CO. A triclosan-resistant bacterial enzyme. Nature406,145–146 (2000).
Medline CASGoogle Scholar
186 Rozwarski DA, Vilcheze C, Sugantino M, Bittman R, Sacchettini JC. Crystal structure of the Mycobacterium tuberculosis enoyl-ACP reductase, InhA, in complex with NAD+ and a C16 fatty acyl substrate. J. Biol. Chem.274(22),15582–15589 (1999).
Medline CASGoogle Scholar
187 Parikh S, Moynihan DP, Xiao G, Tonge PJ. Roles of tyrosine 158 and lysine 165 in the catalytic mechanism of InhA, the enoyl-ACP reductase from Mycobacterium tuberculosis. Biochemistry38(41),13623–13634 (1999).
Medline CASGoogle Scholar
188 Rafi S, Novichenok P, Kolappan S et al. Structure of acyl carrier protein bound to FabI, the FASII enoyl reductase from Escherichia coli. J. Biol. Chem.281(51),39285–39293 (2006).
Medline CASGoogle Scholar
189 Banerjee A, Dubnau E, Quemard A et al. ihA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science263,227–230 (1994).
Medline CASGoogle Scholar
190 Heath RJ, Yu Y-T, Shapiro MA, Olson E, Rock CO. Broad-spectrum antimicrobial biocides target the FabI component of fatty acid synthesis. J. Biol. Chem.273,30316–3032 (1998).
Medline CASGoogle Scholar
191 Baldock C, de Boer GJ, Rafferty JB, Stuitje AR, Rice DW. Mechanism of action of diazaborines. Biochem. Pharm.55,1541–1549 (1998).
Medline CASGoogle Scholar
192 Davis MC, Franzblau SG, Martin AR. Synthesis and evaluation of benzodiazaborine compounds against M. tuberculosis H₃₇R_vin vitro. Bioorg. Med. Chem. Lett.8,843–846 (1998).
Medline CASGoogle Scholar
193 Payne DJ, Miller WH, Berry V et al. Discovery of a novel and potent class of FabI-directed antibacterial agents. Antimicrob. Agents Chemother.46(10),3118–3124 (2002).
Medline CASGoogle Scholar
194 Seefeld MA, Miller WH, Newlander KA et al. Indole naphthyridinones as inhibitors of bacterial enoyl-ACP reductases FabI and FabK. J. Med. Chem.46,1627 (2003).
Medline CASGoogle Scholar
195 Hevener KE, Mehboob S, Su PC et al. Discovery of a novel and potent class of F. tularensis enoyl-reductase (FabI) inhibitors by molecular shape and electrostatic matching. J. Med. Chem.55(1),268–279 (2012).
Medline CASGoogle Scholar
196 Vilcheze C, Jacobs WR Jr. The mechanism of isoniazid killing: clarity through the scope of genetics. Annu. Rev. Microbiol.61,35–50 (2007).
Medline CASGoogle Scholar
197 Mdluli K, Slayden RA, Zhu Y et al. Inhibition of a Mycobacterium tuberculosis -ketoacyl ACP synthase by isoniazid. Science280,1607–1610 (1998).
Medline CASGoogle Scholar
198 Ghosh AK, Xi K. Total synthesis of (-)-platensimycin, a novel antibacterial agent. J. Org. Chem.74(3),1163–1170 (2009).
Medline CASGoogle Scholar
199 Argyrou A, Vetting MW, Aladegbami B, Blanchard JS. Mycobacterium tuberculosisdihydrofolate reductase is a target for isoniazid. Nat. Struct. Mol. Biol.13,408–413 (2006).
Medline CASGoogle Scholar
200 Rouse DA, Li Z, Bai G-H, Morris. SL. Characterization of the katG and inhA genes of isoniazid-resistant clinical isolates of Mycobacterium tuberculosis. Antimicrob. Agents Chemother.39(11),2472–2477 (1995).
Medline CASGoogle Scholar
201 DeBarber AE, Mdluli K, Bosman M, Bekker L-G, Barry CE 3rd. Ethionamide activation and sensitivity in multidrugresistant Mycobacterium tuberculosis. Proc. Natl Acad. Sci. USA97(17),9677–9682 (2000).
Medline CASGoogle Scholar
202 Lu H, Tonge PJ. Inhibitors of FabI, an enzyme drug target in the bacterial fatty acid biosynthesis pathway. Acc. Chem. Res.41(1),11–20 (2008).
Medline CASGoogle Scholar
203 Baldock C, Rafferty JB, Sedelnikova SE et al. A mechanism of drug action revealed by structural studies of enoyl reductase. Science274,2107–2110 (1996).
Medline CASGoogle Scholar
204 Roujeinikova A, Sedelnikova S, de Boer GJ et al. Inhibitor binding studies on enoyl reductase reveal conformational changes related to substrate recognition. J. Biol. Chem.274,30811–30817 (1999).
Medline CASGoogle Scholar
205 de Boer GJ, Pielage GJ, Nijkamp HJ et al. Molecular genetic analysis of enoyl-acyl carrier protein reductase inhibition by diazoborine. Mol. Microbiol.31,443–450 (1999).
Medline CASGoogle Scholar
206 Aiello AE, Larson E. Antibacterial cleaning and hygiene products as an emerging risk factor for antibiotic resistance in the community. Lancet Infect. Dis.3(8),501–506 (2003).
MedlineGoogle Scholar
207 Ward WHJ, Holdgate GA, Rowsell S et al. Kinetic and structural characteristics of the inhibition of enoyl (acyl carrier protein) reductase by triclosan. Biochemistry38,12514–12525 (1999).
Medline CASGoogle Scholar
208 McMurry LM, Oethinger M, Levy SB. Overexpression of marA, soxS, or acrAB produces resistance to triclosan in laboratory and clinical strains of Escherichia coli. FEMS Microbiol. Lett.166,305–309 (1998).
Medline CASGoogle Scholar
209 Sullivan TJ, Truglio JJ, Boyne ME et al. High affinity InhA inhibitors with activity against drug-resistant strains of Mycobacterium tuberculosis. ACS Chem. Biol.1(1),43–53 (2006).
Medline CASGoogle Scholar
210 Sivaraman S, Sullivan TJ, Johnson F et al. Inhibition of the bacterial enoyl reductase FabI by triclosan: a structure-reactivity analysis of FabI inhibition by triclosan analogues. J. Med. Chem.47(3),509–518 (2004).
Medline CASGoogle Scholar
211 Liu BQ, Wang YQ, Fillgrove KL, Anderson VE. Triclosan inhibits enoyl-reductase of type I fatty acid synthase in vitro and is cytotoxic to MCF-7 and SKBr-3 breast cancer cells. Cancer Chemother. Pharmacol.49(3),187–193 (2002).
Medline CASGoogle Scholar
212 Karlowsky JA, Kaplan N, Hafkin B, Hoban DJ, Zhanel GG. AFN-1252, a FabI inhibitor, demonstrates a Staphylococcus-specific spectrum of activity. Antimicrob. Agents Chemother.53(8),3544–3548 (2009).
Medline CASGoogle Scholar
213 Bogdanovich T, Clark C, Kosowska-Shick K, Dewasse B, McGhee P, Appelbaum PC. Antistaphylococcal activity of CG400549, a new experimental FabI inhibitor, compared with that of other agents. Antimicrob. Agents Chemother.51(11),4191–4195 (2007).
Medline CASGoogle Scholar
214 Park HS, Yoon YM, Jung SJ, Kim CM, Kim JM, Kwak JH. Antistaphylococcal activities of CG400549, a new bacterial enoyl-acyl carrier protein reductase (FabI) inhibitor. J. Antimicrob. Chemother.60(3),568–574 (2007).
Medline CASGoogle Scholar
215 Beigneux AP, Kosinski C, Gavino B, Horton JD, Skarnes WC, Young SG. ATP-citrate lyase deficiency in the mouse. J. Biol. Chem.279(10),9557–9564 (2004).
Medline CASGoogle Scholar
216 Sugden MC, Holness MJ. Therapeutic potential of the mammalian pyruvate dehydrogenase kinases in the prevention of hyperglycaemia. Curr. Drug Targets Immune Endocr. Metabol. Disord.2(2),151–165 (2002).
Medline CASGoogle Scholar
217 Bauer DE, Hatzivassiliou G, Zhao FP, Andreadis C, Thompson CB. ATP citrate lyase is an important component of cell growth and transformation. Oncogene24(41),6314–6322 (2005).
Medline CASGoogle Scholar
218 Watson JA, Fang M, Lowenste JM. Tricarballylate and hydroxycitrate - substrate and inhibitor of ATP – citrate oxaloacetate lyase. Arch. Biochem. Biophys.135(1–2),209–217 (1969).
Medline CASGoogle Scholar
219 Heymsfield SB, Allison DB, Vasselli JR, Pietrobelli A, Greenfield D, Nunez C. Garcinia cambogia (hydroxycitric acid) as a potential antiobesity agent – a randomized controlled trial. J. Am. Med. Assoc.280(18),1596–1600 (1998).
CASGoogle Scholar
220 Ohia SE, Opere CA, LeDay AM, Bagchi M, Bagchi D, Stohs SJ. Safety and mechanism of appetite suppression by a novel hydroxycitric acid extract (HCA-SX). Mol. Cell. Biochem.238(1–2),89–103 (2002).
Medline CASGoogle Scholar
221 Pearce NJ, Yates JW, Berkhout TA et al. The role of ATP citrate-lyase in the metabolic regulation of plasma lipids – hypolipidaemic effects of SB-204990, a lactone prodrug of the potent ATP citrate-lyase inhibitor SB-201076. Biochem. J.334,113–119 (1998).
Medline CASGoogle Scholar
222 Ma ZP, Chu CH, Cheng D. A novel direct homogeneous assay for ATP citrate lyase. J. Lipid Res.50(10),2131–2135 (2009).
Medline CASGoogle Scholar
223 Hatzivassiliou G, Zhao FP, Bauer DE et al. ATP citrate lyase inhibition can suppress tumor cell growth. Cancer Cell8(4),311–321 (2005).
Medline CASGoogle Scholar
224 Oleynek JJ, Barrow CJ, Burns MP et al. Anthrones, naturally-occurring competitive inhibitors of adenosine-triphosphate-citrate lyase. Drug Dev. Res.36(1),35–42 (1995).
CASGoogle Scholar
225 Chu KY, Lin Y, Hendel A, Kulpa JE, Brownsey RW, Johnson JD. ATP-citrate lyase reduction mediates palmitate-induced apoptosis in pancreatic beta cells. J. Biol. Chem.285(42),32606–32615 (2010).
Medline CASGoogle Scholar
226 Pemble CWT, Johnson LC, Kridel SJ, Lowther WT. Crystal structure of the thioesterase domain of human fatty acid synthase inhibited by Orlistat. Nat. Struct. Mol. Biol.14(8),704–709 (2007).
Medline CASGoogle Scholar
227 Hadvary P, Sidler W, Meister W, Vetter W, Wolfer H. The lipase inhibitor tetrahydrolipstatin binds covalently to the putative active-site serine of pancreatic lipase. J. Biol. Chem.266(4),2021–2027 (1991).
Medline CASGoogle Scholar
228 Hill JO, Hauptman J, Anderson JW et al. Orlistat, a lipase inhibitor, for weight maintenance after conventional dieting: a 1-y study. Am. J. Clin. Nutr.69(6),1108–1116 (1999).
Medline CASGoogle Scholar
229 Yang PY, Liu K, Ngai MH, Lear MJ, Wenk MR, Yao SQ. Activity-based proteome profiling of potential cellular targets of orlistat – an FDA-approved drug with anti-tumor activities. J. Am. Chem. Soc.132(2),656–666 (2010).
Medline CASGoogle Scholar
230 Martinez-Villaluenga C, Rupasinghe SG, Schuler MA, de Mejia EG. Peptides from purified soybean beta-conglycinin inhibit fatty acid synthase by interaction with the thioesterase catalytic domain. FEBS J.277(6),1481–1493 (2010).
Medline CASGoogle Scholar
231 Richardson RD, Smith JW. Novel antagonists of the thioesterase domain of human fatty acid synthase. Mol. Cancer Ther.6(7),2120–2126 (2007).
Medline CASGoogle Scholar
232 Zhang W, Chakravarty B, Zheng F et al. Crystal structure of FAS thioesterase domain with polyunsaturated fatty acyl adduct and inhibition by dihomo-gamma-linolenic acid. Proc. Natl Acad. Sci. USA108(38),15757–15762 (2011).▪ Demonstrates that dietary long-chain polyunsaturated fatty acids could inhibit thioesterase domain of FAS.
Medline CASGoogle Scholar
233 Grimes KD, Lu YJ, Zhang YM et al. Novel acyl phosphate mimics that target PlsY, an essential acyltransferase in gram-positive bacteria. ChemMedChem3(12),1936–1945 (2008).
Medline CASGoogle Scholar
234 Ramsay RR, Gandour RD, van der Leij FR. Molecular enzymology of carnitine transfer and transport. Biochim. Biophys. Acta1546(1),21–43 (2001).
Medline CASGoogle Scholar
235 Bonnefont JP, Djouadi F, Prip-Buus C, Gobin S, Munnich A, Bastin J. Carnitine palmitoyltransferases 1 and 2: biochemical, molecular and medical aspects. Mol. Aspects Med.25(5–6),495–520 (2004).▪ Review of the history and genetic study of CPT and the medical implication for its deficiency.
Medline CASGoogle Scholar
236 Foster DW. The role of the carnitine system in human metabolism. Ann. NY Acad. Sci.1033,1–16 (2004).
Medline CASGoogle Scholar
237 Kuhajda FP, Ronnett GV. Modulation of carnitine palmitoyltransferase-1 for the treatment of obesity. Curr. Opin. Investig. Drugs8(4),312–317 (2007).
Medline CASGoogle Scholar
238 Ronnett GV, Kleman AM, Kim EK, Landree LE, Tu Y. Fatty acid metabolism, the central nervous system, and feeding. Obesity14(Suppl. 5),201S–207S (2006).
Medline CASGoogle Scholar
239 Anderson RC, Balestra M, Bell PA et al. Antidiabetic agents: a new class of reversible carnitine palmitoyltransferase I inhibitors. J. Med. Chem.38(18),3448–3450 (1995).
Medline CASGoogle Scholar
240 Jenkins DL, Griffith OW. Antiketogenic and hypoglycemic effects of aminocarnitine and acylaminocarnitines. Proc. Natl Acad. Sci. USA83(2),290–294 (1986).
Medline CASGoogle Scholar
241 Giannessi F, Pessotto P, Tassoni E et al. Discovery of a long-chain carbamoyl aminocarnitine derivative, a reversible carnitine palmitoyltransferase inhibitor with antiketotic and antidiabetic activity. J. Med. Chem.46(2),303–309 (2003).
Medline CASGoogle Scholar
242 Rufer AC, Thoma R, Benz J et al. The crystal structure of carnitine palmitoyltransferase 2 and implications for diabetes treatment. Structure14(4),713–723 (2006).
Medline CASGoogle Scholar
243 Anderson RC. Carnitine palmitoyltransferase: a viable target for the treatment of NIDDM? Curr. Pharm. Des.4(1),1–16 (1998).
Medline CASGoogle Scholar
244 Thupari JN, Pinn ML, Kuhajda FP. Fatty acid synthase inhibition in human breast cancer cells leads to malonyl-CoA-induced inhibition of fatty acid oxidation and cytotoxicity. Biochem. Biophys. Res. Commun.285(2),217–223 (2001).
Medline CASGoogle Scholar
245 Altenbern RA. Cerulenin-inhibited cells of Staphylococcus aureus resume growth when supplemented with either a saturated or an unsaturated fatty acid. Antimicrob. Agents Chemother.11,574–576 (1977).
Medline CASGoogle Scholar
246 Brinster S, Lamberet G, Staels B, Trieu-Cuot P, Gruss A, Poyart C. Type II fatty acid synthesis is not a suitable antibiotic target for Gram-positive pathogens. Nature458(7234),83–86 (2009).
Medline CASGoogle Scholar
247 Parsons JB, Frank MW, Subramanian C, Saenkham P, Rock CO. Metabolic basis for the differential susceptibility of Gram-positive pathogens to fatty acid synthesis inhibitors. Proc. Natl Acad. Sci. USA108(37),15378–15383 (2011).
Medline CASGoogle Scholar
248 Jakobsson HE, Jernberg C, Andersson AF, Sjolund-Karlsson M, Jansson JK, Engstrand L. Short-term antibiotic treatment has differing long-term impacts on the human throat and gut microbiome. PLoS ONE5(3),e9836 (2010).
MedlineGoogle Scholar
249 Kau AL, Ahern PP, Griffin NW, Goodman AL, Gordon JI. Human nutrition, the gut microbiome and the immune system. Nature474(7351),327–336 (2011).
Medline CASGoogle Scholar
250 Parker RA, Flint OP, Mulvey R et al. Endoplasmic reticulum stress links dyslipidemia to inhibition of proteasome activity and glucose transport by HIV protease inhibitors. Mol. Pharmacol.67(6),1909–1919 (2005).
Medline CASGoogle Scholar
251 Alexander JW. Immunonutrition: the role of omega-3 fatty acids. Nutrition14(7–8),627–633 (1998).
Medline CASGoogle Scholar
252 Pommerville JC. Fundamentals of Microbiology. Jones & Bartlett Learning, Sudbury, MA, USA, 115 (2008).
Google Scholar
253 Daffé M, Reyrat J-M. The Mycobacterial Cell Envelope. ASM Press, Washington, DC, USA, 4 (2008).
Google Scholar
254 He X, Reeve AM, Desai UR, Kellogg GE, Reynolds KA. 1,2-dithiole-3-ones as potent inhibitors of the bacterial 3-ketoacyl acyl carrier protein synthase III (FabH). Antimicrob. Agents Chemother.48(8),3093 (2004).
Medline CASGoogle Scholar
255 Khandekar SS, Gentry DR, Aller GSV et al. Identification, substrate specificity, and inhibition of the Streptococcus pneumoniae b-ketoacyl-acyl carrier protein synthase III (FabH). J. Biol. Chem.276(32),30024 (2001).
Medline CASGoogle Scholar
256 Noto T, Miyakawa S, Oishi H, Endo H, Okazaki. H. Thiolactomycin, a new antibiotic. III. In vitro antibacterial activity J. Antibiot. (Tokyo)35,401 (1982).
Medline CASGoogle Scholar
257 Rosner JL. Susceptibilities of oxyR regulon mutants of Escherichia coli and Salmonella typhimurium to isoniazid. Antimicrob. Agents Chemother.37,2251–2253 (1993).
Medline CASGoogle Scholar
258 Rawat R, Whitty A, Tonge PJ. The isoniazid-NAD adduct is a slow, tight-binding inhibitor of InhA, the Mycobacterium tuberculosis enoyl reductase: adduct affinity and drug resistance. Proc. Natl Acad. Sci. USA100(24),13881–13886 (2003).
Medline CASGoogle Scholar
259 Baulard AR, Betts JC, Engohang-Ndong J et al. Activation of the pro-drug ethionamide is regulated in Mycobacteria. Proc. Natl Acad. Sci. USA275(36),28326–28331 (2000).
CASGoogle Scholar
260 Wang F, Langley R, Gulten G et al. Mechanism of thioamide drug action against tuberculosis and leprosy. J. Exp. Med.204(1),73–78 (2007).
Medline CASGoogle Scholar
261 Jang KP, Kim CH, Na SW et al. 7-phenylplatensimycin and 11-methyl-7-phenylplatensimycin: more potent analogs of platensimycin. Bioorg. Med. Chem. Lett.20(7),2156–2158 (2009).
Google Scholar
262 Patra M, Gasser G, Pinto A et al. Synthesis and biological evaluation of chromium bioorganometallics based on the antibiotic platensimycin lead structure. ChemMedChem4(11),1930–1938 (2009).
Medline CASGoogle Scholar
263 Tiefenbacher K, Gollner A, Mulzer J. Syntheses and antibacterial properties of iso-platencin, Cl-iso-platencin and Cl-platencin: identification of a new lead structure. Chem. Eur. J.16(31),9616–9622 (2010).
Medline CASGoogle Scholar
264 Jang KP, Kim CH, Na SW, Kim H, Kang H, Lee E. Isoplatensimycin: Synthesis and biological evaluation. Bioorg. Med. Chem. Lett.19(16),4601–4602 (2009).
Medline CASGoogle Scholar
265 Nicolaou KC, Tang Y, Wang J, Stepan AF, Li A, Montero A. Total synthesis and antibacterial properties of carbaplatensimycin. J. Am. Chem. Soc.129(48),14850–14851 (2007).
Medline CASGoogle Scholar
266 Nicolaou KC, Lister T, Denton RM, Montero A, Edmonds DJ. Adamantaplatensimycin: a bioactive analogue of platensimycin. Angew. Chem. Int. Ed. Engl.46(25),4712–4714 (2007).
Medline CASGoogle Scholar
267 Zhang C, Ondeyka J, Herath K et al. Platensimycin and platencin congeners from Streptomyces platensis. J. Nat. Prod.74(3),329–340 (2011).
Medline CASGoogle Scholar
268 Singh SB, Jayasuriya H, Ondeyka JG et al. Isolation, structure, and absolute stereochemistry of platensimycin, a broad spectrum antibiotic discovered using an antisense differential sensitivity strategy. J. Am. Chem. Soc.128(36),11916–11920 (2006).
Medline CASGoogle Scholar
269 Zhang CW, Ondeyka J, Zink DL, Burgess B, Wang J, Singh SB. Isolation, structure and fatty acid synthesis inhibitory activities of platensimycin B-1-B-3 from Streptomyces platensis. Chem. Comm. (40),5034–5036 (2008).
MedlineGoogle Scholar
270 Wang J, Sintim HO. Dialkylamino-2,4-dihydroxybenzoic acids as easily synthesized analogues of platensimycin and platencin with comparable antibacterial properties. Chem. Eur. J.17(12),3352–3357 (2011).
Medline CASGoogle Scholar
271 Barykina OV, Rossi KL, Rybak MJ, Snider BB. Synthesis and antibacterial properties of (-)-nor-platencin. Org. Lett.11(22),5334–5337 (2009).
Medline CASGoogle Scholar
272 Singh SB, Jayasuriya H, Herath KB et al. Isolation, enzyme-bound structure, and activity of platensimycin A1 from Streptomyces platensis. Tetra. Lett.50(37),5182–5185 (2009).
CASGoogle Scholar
273 Zhang CW, Ondeyka J, Guan ZQ et al. Isolation, structure and biological activities of platensimycin B-4 from Streptomyces platensis. J. Antibiotics62(12),699–702 (2009).
Medline CASGoogle Scholar

Vol. 4, No. 9

Metrics

Downloaded 343 times

History

Published online 18 June 2012

Published in print June 2012

Information

Disclaimer

The opinions expressed in this review do not necessarily reflect those of Theravance, Inc.

Financial & competing interests disclosure

The authors wish to thank the Camille Dreyfus Foundation for funding to HO Sintim. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

PDF download