具有体内活性的基于硫内酯霉素的细菌β-酮酰基-ACP合酶抑制剂。
Thiolactomycin-Based Inhibitors of Bacterial β-Ketoacyl-ACP Synthases with in Vivo Activity.
作者信息
Bommineni Gopal R, Kapilashrami Kanishk, Cummings Jason E, Lu Yang, Knudson Susan E, Gu Chendi, Walker Stephen G, Slayden Richard A, Tonge Peter J
机构信息
Department of Microbiology, Immunology and Pathology, Colorado State University , Fort Collins, Colorado 80523-2025, United States.
出版信息
J Med Chem. 2016 Jun 9;59(11):5377-90. doi: 10.1021/acs.jmedchem.6b00236. Epub 2016 May 24.
Abstract
β-Ketoacyl-ACP synthases (KAS) are key enzymes involved in the type II bacterial fatty acid biosynthesis (FASII) pathway and are putative targets for antibacterial discovery. Several natural product KAS inhibitors have previously been reported, including thiolactomycin (TLM), which is produced by Nocardia spp. Here we describe the synthesis and characterization of optically pure 5R-thiolactomycin (TLM) analogues that show improved whole cell activity against bacterial strains including methicillin-resistant Staphylococcus aureus (MRSA) and priority pathogens such as Francisella tularensis and Burkholderia pseudomallei. In addition, we identify TLM analogues with in vivo efficacy against MRSA and Klebsiella pneumoniae in animal models of infection.
摘要
β-酮脂酰-ACP合成酶（KAS）是参与II型细菌脂肪酸生物合成（FASII）途径的关键酶，是抗菌药物研发的潜在靶点。此前已报道了几种天然产物KAS抑制剂，包括诺卡氏菌属产生的硫内酯霉素（TLM）。在此，我们描述了光学纯的5R-硫内酯霉素（TLM）类似物的合成与表征，这些类似物对包括耐甲氧西林金黄色葡萄球菌（MRSA）以及诸如土拉弗朗西斯菌和类鼻疽伯克霍尔德菌等重点病原体在内的细菌菌株显示出更高的全细胞活性。此外，我们还鉴定出了在感染动物模型中对MRSA和肺炎克雷伯菌具有体内疗效的TLM类似物。
相似文献
1
Thiolactomycin-Based Inhibitors of Bacterial β-Ketoacyl-ACP Synthases with in Vivo Activity.
J Med Chem. 2016 Jun 9;59(11):5377-90. doi: 10.1021/acs.jmedchem.6b00236. Epub 2016 May 24.
2
Novel E. coli beta-ketoacyl-acyl carrier protein synthase III inhibitors as targeted antibiotics.
Bioorg Med Chem. 2009 Feb 15;17(4):1506-13. doi: 10.1016/j.bmc.2009.01.004. Epub 2009 Jan 11.
3
Slow onset inhibition of bacterial beta-ketoacyl-acyl carrier protein synthases by thiolactomycin.
J Biol Chem. 2010 Feb 26;285(9):6161-9. doi: 10.1074/jbc.M109.077909. Epub 2009 Dec 16.
4
Purification, characterization, and identification of novel inhibitors of the beta-ketoacyl-acyl carrier protein synthase III (FabH) from Staphylococcus aureus.
Antimicrob Agents Chemother. 2002 May;46(5):1310-8. doi: 10.1128/AAC.46.5.1310-1318.2002.
5
Structural and biological evaluation of a novel series of benzimidazole inhibitors of Francisella tularensis enoyl-ACP reductase (FabI).
Bioorg Med Chem Lett. 2015 Mar 15;25(6):1292-6. doi: 10.1016/j.bmcl.2015.01.048. Epub 2015 Jan 29.
6
Discovery of novel selective inhibitors of Staphylococcus aureus β-ketoacyl acyl carrier protein synthase III.
Eur J Med Chem. 2012 Jan;47(1):261-9. doi: 10.1016/j.ejmech.2011.10.052. Epub 2011 Nov 4.
7
Bacterial beta-ketoacyl-acyl carrier protein synthases as targets for antibacterial agents.
Curr Protein Pept Sci. 2003 Feb;4(1):21-9. doi: 10.2174/1389203033380377.
8
Novel inhibitors of the condensing enzymes of the type II fatty acid synthase of pea (Pisum sativum).
Biochem J. 2000 Apr 1;347 Pt 1(Pt 1):205-9.
9
Synthesis and structure-activity relationships of thiotetronic acid analogues of thiolactomycin.
Bioorg Med Chem Lett. 2001 Oct 22;11(20):2751-4. doi: 10.1016/s0960-894x(01)00567-4.
10
Biphenyl-based analogues of thiolactomycin, active against Mycobacterium tuberculosis mtFabH fatty acid condensing enzyme.
Bioorg Med Chem Lett. 2003 Nov 3;13(21):3685-8. doi: 10.1016/j.bmcl.2003.08.015.
引用本文的文献
1
Unlocking Lactonase Enzymes as Biocatalysts for the Deracemisation of Chiral γ-Thiolactones.
Angew Chem Int Ed Engl. 2025 Jul;64(29):e202505032. doi: 10.1002/anie.202505032. Epub 2025 May 29.
2
Lipid-Centric Approaches in Combating Infectious Diseases: Antibacterials, Antifungals and Antivirals with Lipid-Associated Mechanisms of Action.
Antibiotics (Basel). 2023 Dec 11;12(12):1716. doi: 10.3390/antibiotics12121716.
3
Activity of Novel Topoisomerase Inhibitors against and .
Antibiotics (Basel). 2023 May 30;12(6):983. doi: 10.3390/antibiotics12060983.
4
Combating Antimicrobial Resistance in the Post-Genomic Era: Rapid Antibiotic Discovery.
Molecules. 2023 May 19;28(10):4183. doi: 10.3390/molecules28104183.
5
KasA as a drug target: Structure-based inhibitor design.
Front Cell Infect Microbiol. 2022 Sep 15;12:1008213. doi: 10.3389/fcimb.2022.1008213. eCollection 2022.
6
Anti-Tubercular Properties of 4-Amino-5-(4-Fluoro-3- Phenoxyphenyl)-4-1,2,4-Triazole-3-Thiol and Its Schiff Bases: Computational Input and Molecular Dynamics.
Antibiotics (Basel). 2020 Aug 31;9(9):559. doi: 10.3390/antibiotics9090559.
7
Synthesis and crystal structures of 3-hy-droxy-2,4-dimethyl-2-thio-phen-5-one and 3-hy-droxy-4-methyl-2-thio-phen-5-one.
Acta Crystallogr E Crystallogr Commun. 2020 Jun 30;76(Pt 7):1158-1162. doi: 10.1107/S2056989020008269. eCollection 2020 Jul 1.
8
Emerging role of biologics for the treatment of melioidosis and glanders.
Expert Opin Biol Ther. 2019 Dec;19(12):1319-1332. doi: 10.1080/14712598.2019.1677602. Epub 2019 Oct 15.
9
Synthesis, bioactivity, and enzymatic modification of antibacterial thiotetromycin derivatives.
Org Biomol Chem. 2019 Mar 27;17(13):3416-3423. doi: 10.1039/c8ob03109f.
10
Design, synthesis, and biological evaluation of novel benzimidazole tethered allylidenehydrazinylmethylthiazole derivatives as potent inhibitors of .
Medchemcomm. 2018 Oct 25;10(1):49-60. doi: 10.1039/c8md00389k. eCollection 2019 Jan 1.
本文引用的文献
1
Activity of Debio1452, a FabI inhibitor with potent activity against Staphylococcus aureus and coagulase-negative Staphylococcus spp., including multidrug-resistant strains.
Antimicrob Agents Chemother. 2015 May;59(5):2583-7. doi: 10.1128/AAC.05119-14. Epub 2015 Feb 17.
2
Structural basis for the recognition of mycolic acid precursors by KasA, a condensing enzyme and drug target from Mycobacterium tuberculosis.
J Biol Chem. 2013 Nov 22;288(47):34190-34204. doi: 10.1074/jbc.M113.511436. Epub 2013 Oct 9.
3
Thiolactomycin-based β-ketoacyl-AcpM synthase A (KasA) inhibitors: fragment-based inhibitor discovery using transient one-dimensional nuclear overhauser effect NMR spectroscopy.
J Biol Chem. 2013 Mar 1;288(9):6045-52. doi: 10.1074/jbc.M112.414516. Epub 2013 Jan 10.
4
Fatty acid biosynthesis in Pseudomonas aeruginosa is initiated by the FabY class of β-ketoacyl acyl carrier protein synthases.
J Bacteriol. 2012 Oct;194(19):5171-84. doi: 10.1128/JB.00792-12. Epub 2012 Jun 29.
5
Substrate recognition by β-ketoacyl-ACP synthases.
Biochemistry. 2011 Dec 13;50(49):10678-86. doi: 10.1021/bi201199x. Epub 2011 Nov 17.
6
The MUT056399 inhibitor of FabI is a new antistaphylococcal compound.
Antimicrob Agents Chemother. 2011 Oct;55(10):4692-7. doi: 10.1128/AAC.01248-10. Epub 2011 Aug 8.
7
Synthesis of and tautomerism in 3-acyltetramic acids.
J Org Chem. 2011 Mar 4;76(5):1342-54. doi: 10.1021/jo102304y. Epub 2011 Jan 20.
8
Slow onset inhibition of bacterial beta-ketoacyl-acyl carrier protein synthases by thiolactomycin.
J Biol Chem. 2010 Feb 26;285(9):6161-9. doi: 10.1074/jbc.M109.077909. Epub 2009 Dec 16.
9
Synthesis and biological activity of enantiomeric pairs of 5-(Alk-2-enyl)thiolactomycin and 5-[(E)-Cycloalk-2-enylidenemethyl]thiolactomycin congeners.
Chem Pharm Bull (Tokyo). 2009 Sep;57(9):920-36. doi: 10.1248/cpb.57.920.
10
Crystal structures of Mycobacterium tuberculosis KasA show mode of action within cell wall biosynthesis and its inhibition by thiolactomycin.
Structure. 2009 Jul 15;17(7):1004-13. doi: 10.1016/j.str.2009.04.012.
Zotero 插件