Covalent Inhibitors Targeting FabH: A Cutting-edge Strategy in the Development of Novel Antibiotics
DOI:
https://doi.org/10.62051/gvs2pj23Keywords:
Antibiotic resistance; Fatty acid synthesis; FabH; FabH inhibitor; Covalent inhibitor; Development of antibacterial drugs.Abstract
Antibiotic resistance has become a global public health crisis, and there is an urgent need to develop new mechanism antibacterial drugs targeting specific targets of bacteria. β -ketoacyl-ACP synthase Ⅲ (FabH) inhibitors have shown great potential to overcome bacterial resistance and have become an emerging hot field in the research and development of anti-infective drugs. And unlike traditional reversible inhibitors (relying on transient non-covalent interactions), covalent inhibitors can form stable covalent bonds to achieve irreversible inhibition of the target. This combination method brings significant advantages (such as long-term effectiveness and high efficiency, etc.). This article systematically reviews the uniqueness of FabH, analyzes the chemical structure and application of representative covalent inhibitors of FabH, dissects the mechanism of action of covalent inhibitors and the clinical evidence that FabH can be used as a covalent inhibitory target. The research on covalent inhibitors based on FabH provides a promising new approach for the development of the next generation of novel antibiotics that are highly efficient, narrow-spectrum and less prone to drug resistance.
Downloads
References
[1] World Health Organization. Antimicrobial resistance global report on surveillance: 2014 summary[J]. 2014.
[2] GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020 Oct 17;396(10258):1204-1222.
[3] O'NEILL J. Tackling a crisis for the health and wealth of nation[J]. Review on antimicrobial resistance，2014, 20：1-16.
[4] Liu Xiaobo, Li Yuyan, You Qidong. Research progress of β-ketoacyl-ACP synthase (FabH) inhibitors[J]. Progress in Chemistry, 2009, 21(09): 1930-1938.
[5] Bibens L, Becker JP, Dassonville-Klimpt A, Sonnet P. A Review of Fatty Acid Biosynthesis Enzyme Inhibitors as Promising Antimicrobial Drugs. Pharmaceuticals (Basel). 2023 Mar 10;16(3):425.
[6] Wang Jiajie Research on Microbial Bactericidal Active Substances Based on FabH immobilized Affinity Chromatography [D]. Nanjing Agricultural University,2018.
[7] Zhang Xuehui, Yu Hong, Wang Lili, et al. Research Progress on New Antibacterial Drug Targets FabH and Their Inhibitors [J]. Foreign Medicine. Pharmacy Volume,2006,(04):262-265.
[8] Lv S, Zhang Y, Song J, Chen J, Huang B, Luo Y, Zhao Y. Cerulenin suppresses ErbB2-overexpressing breast cancer by targeting ErbB2/PKM2 pathway. Med Oncol. 2022 Oct 29;40(1):5.
[9] Zhou Yang, Liu Zhili, Shu Yong, et al. The inhibitory effect of light cyanobacteritin on the growth of human osteosarcoma cell line U2-OS in nude mice [J]. Journal of Nanchang University (Medical Science Edition),2010,50(03):16-19+24+139.
[10] Tian Kai, Deng Youchao, Li Yuling, et al. Research Progress on Biosynthesis, Total Synthesis and Semi-synthesis of Platinamycin and platinamycin and Their Derivatives [J]. Organic Chemistry,2018,38(09):2348-2362.
[11] Jayasuriya H, Herath KB, Zhang C, Zink DL, Basilio A, Genilloud O, Diez MT, Vicente F, Gonzalez I, Salazar O, Pelaez F, Cummings R, Ha S, Wang J, Singh SB. Isolation and structure of platencin: a FabH and FabF dual inhibitor with potent broad-spectrum antibiotic activity. Angew Chem Int Ed Engl. 2007;46(25):4684-8.
[12] Khandekar SS, Daines RA, Lonsdale JT. Bacterial beta-ketoacyl-acyl carrier protein synthases as targets for antibacterial agents. Curr Protein Pept Sci. 2003 Feb;4(1):21-9.
[13] Kumar A, D'Souza SS, Gaonkar SL, Rai KM, Salimath BP. Growth inhibition and induction of apoptosis in MCF-7 breast cancer cells by a new series of substituted-1,3,4-oxadiazole derivatives. Invest New Drugs. 2008 Oct;26(5):425-35.
[14] Luo Y, Zhang LR, Hu Y, Zhang S, Fu J, Wang XM, Zhu HL. Synthesis and antimicrobial activities of oximes derived from O-benzylhydroxylamine as FabH inhibitors. ChemMedChem. 2012 Sep;7(9):1587-93.
[15] Kosmalski T, Hetmann A, Studzińska R, Baumgart S, Kupczyk D, Roszek K. The Oxime Ethers with Heterocyclic, Alicyclic and Aromatic Moiety as Potential Anti-Cancer Agents. Molecules. 2022 Feb 17;27(4):1374.
[16] Wang Yujing, Liu Shunying. The latest Research progress of Targeted covalent inhibitors [J]. Journal of Huanggang Normal University,2020,40(03):50-56.
[17] Singh J, Petter RC, Baillie TA, Whitty A. The resurgence of covalent drugs. Nat Rev Drug Discov. 2011 Apr;10(4):307-17.
[18] Wang Aoxue, Pei Junping, Wang Guan, et al. Research Progress of Covalent inhibitors Targeting Specific amino Acids [J]. Pharmaceutical Progress,2022,46(01):33-46.
[19] Tuley A, Fast W. The Taxonomy of Covalent Inhibitors. Biochemistry. 2018 Jun 19;57(24):3326-3337.
[20] Wang J, Ye X, Yang X, Cai Y, Wang S, Tang J, Sachdeva M, Qian Y, Hu W, Leeds JA, Yuan Y. Discovery of Novel Antibiotics as Covalent Inhibitors of Fatty Acid Synthesis. ACS Chem Biol. 2020 Jul 17;15(7):1826-1834.
Downloads
Published
Issue
Section
License
Copyright (c) 2025 Transactions on Materials, Biotechnology and Life Sciences
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
