• 中国中文核心期刊
  • 中国科学引文数据库核心期刊
  • 中国科技核心期刊
  • 中国高校百佳科技期刊
高级检索

螯合剂类金属β-内酰胺酶抑制剂的研究进展

朱致熹, 张洁琳, 陈依军

朱致熹, 张洁琳, 陈依军. 螯合剂类金属β-内酰胺酶抑制剂的研究进展[J]. 中国药科大学学报, 2022, 53(4): 410-422. DOI: 10.11665/j.issn.1000-5048.20220404
引用本文: 朱致熹, 张洁琳, 陈依军. 螯合剂类金属β-内酰胺酶抑制剂的研究进展[J]. 中国药科大学学报, 2022, 53(4): 410-422. DOI: 10.11665/j.issn.1000-5048.20220404
ZHU Zhixi, ZHANG Jielin, CHEN Yijun. Recent advances in research on chelators as metallo-β-lactamase inhibitors[J]. Journal of China Pharmaceutical University, 2022, 53(4): 410-422. DOI: 10.11665/j.issn.1000-5048.20220404
Citation: ZHU Zhixi, ZHANG Jielin, CHEN Yijun. Recent advances in research on chelators as metallo-β-lactamase inhibitors[J]. Journal of China Pharmaceutical University, 2022, 53(4): 410-422. DOI: 10.11665/j.issn.1000-5048.20220404

螯合剂类金属β-内酰胺酶抑制剂的研究进展

基金项目: 国家自然科学基金资助项目(No.82003627);江苏省自然科学基金资助项目(No.BK20200565)

Recent advances in research on chelators as metallo-β-lactamase inhibitors

Funds: This study was supported by the National Natural Science Foundation of China (No.82003627) and the Natural Science Foundation of Jiangsu Province (No.BK20200565)
  • 摘要: 革兰氏阴性菌对β-内酰胺类抗生素产生耐药的主要机制为表达β-内酰胺酶。金属β-内酰胺酶(metallo-β-lactamases,MBL)可以水解包括碳青霉烯类在内的几乎全部β-内酰胺类抗生素,成为全球公共健康挑战。开发MBL的抑制剂是应对产MBL耐药菌感染的重要手段。螯合剂构成一类重要的MBL抑制剂,通过螯合、剥离、结合MBL活性中心的Zn2+以发挥对MBL的抑制作用。本文综述了螯合剂类MBL抑制剂的研究进展,介绍包括EDTA及其相关化合物、aspergillomarasmine A(AMA)及其衍生物、NOTA及相关化合物、吡啶羧酸类及吡啶甲基胺类化合物在内的几类重要螯合剂类MBL抑制剂的化学结构、抑制活性、与抗生素的协同作用、选择性和作用机制,为后续开发高活性、高选择性和低毒性的MBL抑制剂提供参考。
    Abstract: The major reason for the resistance of Gram-negative bacteria to β-lactam antibiotics is the expression of β-lactamases.Metallo-β-lactamases (MBL) hydrolyze almost all types of β-lactam antibiotics including carbapenems, posing a challenge to global public health. Developing MBL inhibitors is an important method to treat the infections caused by resistant bacteria. As an important type of MBL inhibitors, chelating agents can inhibit MBL by chelating, stripping, and binding Zn2+ in the active center of MBL.This review summarizes recent publications on chelators as MBL inhibitors, discussing their chemical structures, inhibitory potency, synergistic effects with antibiotics, selectivity and mechanism of action, including EDTA and related compounds, aspergillomarasmine A (AMA) and its derivatives, NOTA and related compounds, pyridine carboxylic acid and pyridine methylamine compounds, aiming to provide reference for future development of potent, selective and safe clinical MBL inhibitors.
  • [1] . Cold Spring Harb Perspect Med,2016,6(8):a025247.
    [2] Lutgring JD. Carbapenem-resistant Enterobacteriaceae:an emerging bacterial threat[J]. Semin Diagn Pathol,2019,36(3):182-186.
    [3] Kadri SS. Key takeaways from the US CDC's 2019 antibiotic resistance threats report for frontline providers[J]. Crit Care Med,2020,48(7):939-945.
    [4] Salahuddin P,Kumar A,Khan AU. Structure,function of serine and metallo-β-lactamases and their inhibitors[J]. Curr Protein Pept Sci,2018,19(2):130-144.
    [5] von Nussbaum F,Schiffer G. Aspergillomarasmine A,an inhibitor of bacterial metallo-β-lactamases conferring blaNDM and blaVIM resistance[J]. Angew Chem Int Ed Engl,2014,53(44):11696-11698.
    [6] Linciano P,Cendron L,Gianquinto E,et al. Ten years with New Delhi metallo-β-lactamase-1 (NDM-1):from structural insights to inhibitor design[J]. ACS Infect Dis,2019,5(1):9-34.
    [7] Yamaguchi Y,Kato K,Ichimaru Y,et al. Crystal structures of metallo-β-lactamase (IMP-1) and its D120E mutant in complexes with citrate and the inhibitory effect of the benzyl group in citrate monobenzyl ester[J]. J Med Chem,2021,64(14):10019-10026.
    [8] Pemberton OA,Jaishankar P,Akhtar A,et al. Heteroaryl phosphonates as noncovalent inhibitors of both serine- and metallocarbapenemases[J]. J Med Chem,2019,62(18):8480-8496.
    [9] Rivière G,Oueslati S,Gayral M,et al. NMR characterization of the influence of zinc(II) ions on the structural and dynamic behavior of the New Delhi metallo-β-lactamase-1 and on the binding with flavonols as inhibitors[J]. ACS Omega,2020,5(18):10466-10480.
    [10] Tooke CL,Hinchliffe P,Bragginton EC,et al. β-lactamases and β-lactamase inhibitors in the 21st century[J]. J Mol Biol,2019,431(18):3472-3500.
    [11] Bonomo RA. β-lactamases:a focus on current challenges[J]. Cold Spring Harb Perspect Med,2017,7(1):a025239.
    [12] Elder DP,Kuentz M,Holm R. Antibiotic resistance:the need for a global strategy[J]. J Pharm Sci,2016,105(8):2278-2287.
    [13] Bahr G,González LJ,Vila AJ. Metallo-β-lactamases in the age of multidrug resistance:from structure and mechanism to evolution,dissemination,and inhibitor design[J]. Chem Rev,2021,121(13):7957-8094.
    [14] Sabath LD,Abraham EP. Zinc as a cofactor for cephalosporinase from Bacillus cereus 569[J]. Biochem J,1966,98(1):11C-13C.
    [15] Sychantha D,Rotondo CM,Tehrani KHME,et al. Aspergillomarasmine A inhibits metallo-β-lactamases by selectively sequestering Zn2+[J]. J Biol Chem,2021,297(2):100918.
    [16] Chen AY,Thomas PW,Stewart AC,et al. Dipicolinic acid derivatives as inhibitors of New Delhi metallo-β-lactamase-1[J]. J Med Chem,2017,60(17):7267-7283.
    [17] Thomas DJ,Chisolm JJr. Lead,zinc and copper decorporation during calcium disodium ethylenediamine tetraacetate treatment of lead-poisoned children[J]. J Pharmacol Exp Ther,1986,239(3):829-835.
    [18] Aoki N,Ishii Y,Tateda K,et al. Efficacy of calcium-EDTA as an inhibitor for metallo-β-lactamase in a mouse model of Pseudomonas aeruginosa pneumonia[J]. Antimicrob Agents Chemother,2010,54(11):4582-4588.
    [19] Yoshizumi A,Ishii Y,Livermore DM,et al. Efficacies of calcium-EDTA in combination with imipenem in a murine model of sepsis caused by Escherichia coli with NDM-1 β-lactamase[J]. J Infect Chemother,2013,19(5):992-995.
    [20] Spohn M,Wohlleben W,Stegmann E. Elucidation of the zinc-dependent regulation in Amycolatopsis japonicum enabled the identification of the ethylenediamine-disuccinate ([S,S]-EDDS) genes[J]. Environ Microbiol,2016,18(4):1249-1263.
    [21] Proschak A,Kramer J,Proschak E,et al. Bacterial zincophore [S,S]-ethylenediamine-N,N'-disuccinic acid is an effective inhibitor of MBLs[J]. J Antimicrob Chemother,2018,73(2):425-430.
    [22] Tehrani KHME,Fu HG,Brüchle NC,et al. Aminocarboxylic acids related to aspergillomarasmine A (AMA) and ethylenediamine-N,N'-disuccinic acid (EDDS) are strong zinc-binders and inhibitors of the metallo-beta-lactamase NDM-1[J]. Chem Commun,2020,56(20):3047-3049.
    [23] Haenni AL,Robert M,Vetter W,et al. Structure chimique des aspergillomarasmines A et B[J]. Helv Chim Acta,1965,48(4):729-750.
    [24] Mikami Y,Suzuki T. Novel microbial inhibitors of angiotensin-converting enzyme,aspergillomarasmines A and B[J]. Agric Biol Chem,1983,47(11):2693-2695.
    [25] King AM,Reid-Yu SA,Wang WL,et al. Aspergillomarasmine A overcomes metallo-β-lactamase antibiotic resistance[J]. Nature,2014,510(7506):503-506.
    [26] Rotondo CM,Sychantha D,Koteva K,et al. Suppression of β-lactam resistance by aspergillomarasmine A is influenced by both the metallo-β-lactamase target and the antibiotic partner[J]. Antimicrob Agents Chemother,2020,64(4):e01386- e01419.
    [27] Bergstrom A,Katko A,Adkins Z,et al. Probing the interaction of aspergillomarasmine A with metallo-β-lactamases NDM-1,VIM-2,and IMP-7[J]. ACS Infect Dis,2018,4(2):135-145.
    [28] Liao DH,Yang SQ,Wang JY,et al. Total synthesis and structural reassignment of aspergillomarasmine A[J]. Angew Chem Int Ed Engl,2016,55(13):4291-4295.
    [29] Koteva K,King AM,Capretta A,et al. Total synthesis and activity of the metallo-β-lactamase inhibitor aspergillomarasmine A[J]. Angew Chem Int Ed Engl,2016,55(6):2210-2212.
    [30] Zhang J,Wang SS,Bai YJ,et al. Total syntheses of natural metallophores staphylopine and aspergillomarasmine A[J]. J Org Chem,2017,82(24):13643-13648.
    [31] Albu SA,Koteva K,King AM,et al. Total synthesis of aspergillomarasmine A and related compounds:a sulfamidate approach enables exploration of structure-activity relationships[J]. Angew Chem Int Ed Engl,2016,55(42):13259-13262.
    [32] Fu HG,Zhang JL,Saifuddin M,et al. Chemoenzymatic asymmetric synthesis of the metallo-β-lactamase inhibitor aspergillomarasmine A and related aminocarboxylic acids[J]. Nat Catal,2018,1(3):186-191.
    [33] Guo QQ,Wu DS,Gao L,et al. Identification of the AMA synthase from the aspergillomarasmine A biosynthesis and evaluation of its biocatalytic potential[J]. ACS Catal,2020,10(11):6291-6298.
    [34] Zhang J,Wang SS,Wei Q,et al. Synthesis and biological evaluation of aspergillomarasmine A derivatives as novel NDM-1 inhibitor to overcome antibiotics resistance[J]. Bioorg Med Chem,2017,25(19):5133-5141.
    [35] Somboro AM,Tiwari D,Bester LA,et al. NOTA:a potent metallo-β-actamase inhibitor[J]. J Antimicrob Chemother,2015,70(5):1594-1596.
    [36] Zhang E,Wang MM,Huang SC,et al. NOTA analogue:a first dithiocarbamate inhibitor of metallo-β-lactamases[J]. Bioorg Med Chem Lett,2018,28(2):214-221.
    [37] Li XS,Gui R,Li J,et al. Novel multifunctional silver nanocomposite serves as a resistance-reversal agent to synergistically combat carbapenem-resistant Acinetobacter baumannii[J]. ACS Appl Mater Interfaces,2021,13(26):30434-30457.
    [38] Evans GW,Johnson PE. Characterization and quantitation of a zinc-binding ligand in human milk[J]. Pediatr Res,1980,14(7):876-880.
    [39] Horsfall LE,Garau G,Liénard BMR,et al. Competitive inhibitors of the CphA metallo-β-lactamase from Aeromonas hydrophila[J]. Antimicrob Agents Chemother,2007,51(6):2136-2142.
    [40] Niu XD,Wang XY,Gao YW,et al. Insight into the inhibition mechanism and structure-activity relationship of 2,6-dipicolinic acid and its analogue to New Delhi metallo-β-lactamase-1[J]. Mol Simulat,2019,45(6):525-531.
    [41] Hinchliffe P,Tanner CA,Krismanich AP,et al. Structural and kinetic studies of the potent inhibition of metallo-β-lactamases by 6-phosphonomethylpyridine-2-carboxylates[J]. Biochemistry,2018,57(12):1880-1892.
    [42] Chen AY,Thomas PW,Cheng ZS,et al. Investigation of dipicolinic acid isosteres for the inhibition of metallo-β-lactamases[J]. ChemMedChem,2019,14(13):1271-1282.
    [43] Boros E,Ferreira CL,Cawthray JF,et al. Acyclic chelate with ideal properties for 68Ga PET imaging agent elaboration[J]. J Am Chem Soc,2010,132(44):15726-15733.
    [44] Shi XF,Wang MM,Huang SC,et al. H2depda:an acyclic adjuvant potentiates meropenem activity in vitro against metallo-β-lactamase-producing enterobacterales[J]. Eur J Med Chem,2019,167:367-376.
    [45] Cui DY,Yang Y,Bai MM,et al. Systematic research of H2dedpa derivatives as potent inhibitors of New Delhi metallo-β-lactamase-1[J]. Bioorg Chem,2020,101:103965.
    [46] Chen FF,Bai MM,Liu WT,et al. H2dpa derivatives containing pentadentate ligands:an acyclic adjuvant potentiates meropenem activity in vitro and in vivo against metallo-β-lactamase-producing enterobacterales[J]. Eur J Med Chem,2021,224:113702.
    [47] Azumah R,Dutta J,Somboro AM,et al. In vitro evaluation of metal chelators as potential metallo‐β‐lactamase inhibitors[J]. J Appl Microbiol,2016,120(4):860-867.
    [48] Sosibo SC,Somboro AM,Amoako DG,et al. Impact of pyridyl moieties on the inhibitory properties of prominent acyclic metal chelators against metallo-β-lactamase-producing Enterobacteriaceae:investigating the molecular basis of acyclic metal chelators' activity[J]. Microb Drug Resist,2019,25(3):439-449.
    [49] Schnaars C,Kildahl-Andersen G,Prandina A,et al. Synthesis and preclinical evaluation of TPA-based zinc chelators as metallo-β-lactamase inhibitors[J]. ACS Infect Dis,2018,4(9):1407-1422.
    [50] Wang MM,Chu WC,Yang Y,et al. Dithiocarbamates:efficient metallo-β-lactamase inhibitors with good antibacterial activity when combined with meropenem[J]. Bioorg Med Chem Lett,2018,28(21):3436-3440.
    [51] King DT,Strynadka NCJ. Targeting metallo-β-lactamase enzymes in antibiotic resistance[J]. Future Med Chem,2013,5(11):1243-1263.
    [52] Panlilio H,Lam AK,Heydarian N,et al. Dual-function potentiation by PEG-BPEI restores activity of carbapenems and penicillins against carbapenem-resistant Enterobacteriaceae[J]. ACS Infect Dis,2021,7(6):1657-1665.
    [53] Shin WS,Nguyen ME,Bergstrom A,et al. Fragment-based screening and hit‐based substructure search:rapid discovery of 8‐hydroxyquinoline‐7‐carboxylic acid as a low‐cytotoxic,nanomolar metallo β‐lactamase inhibitor[J]. Chem Biol Drug Des,2021,98(4):481-492.
    [54] Falconer SB,Reid-Yu SA,King AM,et al. Zinc chelation by a small-molecule adjuvant potentiates meropenem activity in vivo against NDM-1-producing Klebsiella pneumoniae[J]. ACS Infect Dis,2015,1(11):533-543.
    [55] Ishii Y,Eto M,Mano Y,et al. In vitro potentiation of carbapenems with ME1071,a novel metallo-β-lactamase inhibitor,against metallo-β-lactamase-producing Pseudomonas aeruginosa clinical isolates[J]. Antimicrob Agents Chemother,2010,54(9):3625-3629.
    [56] Livermore DM,Mushtaq S,Morinaka A,et al. Activity of carbapenems with ME1071 (disodium 2,3-diethylmaleate) against Enterobacteriaceae and Acinetobacter spp. with carbapenemases,including NDM enzymes[J]. J Antimicrob Chemother,2013,68(1):153-158.
    [57] Legru A,Verdirosa F,Hernandez JF,et al. 1,2,4-Triazole-3-thione compounds with a 4-ethyl alkyl/aryl sulfide substituent are broad-spectrum metallo-β-lactamase inhibitors with re-sensitization activity[J]. Eur J Med Chem,2021,226:113873.
    [58] Gavara L,Verdirosa F,Legru A,et al. 4-(N-alkyl-and-acyl-amino)-1,2,4-triazole-3-thione analogs as metallo-β-lactamase inhibitors:impact of 4-linker on potency and spectrum of inhibition[J]. Biomolecules,2020,10(8):1094.
    [59] Gavara L,Legru A,Verdirosa F,et al. 4-Alkyl-1,2,4-triazole-3-thione analogues as metallo-β-lactamase inhibitors[J]. Bioorg Chem,2021,113:105024.
    [60] Shaaban MM,Ragab HM,Akaji K,et al. Design,synthesis,biological evaluation and in silico studies of certain aryl sulfonyl hydrazones conjugated with 1,3-diaryl pyrazoles as potent metallo-β-lactamase inhibitors[J]. Bioorg Chem,2020,105:104386.
    [61] Prandina A,Radix S,le Borgne M,et al. Synthesis and biological evaluation of new dipicolylamine zinc chelators as metallo-β-lactamase inhibitors[J]. Tetrahedron,2019,75(11):1525-1540.
计量
  • 文章访问数: 
  • HTML全文浏览量:  0
  • PDF下载量: 
  • 被引次数: 0
出版历程
  • 收稿日期:  2022-01-27
  • 修回日期:  2022-05-22
  • 刊出日期:  2022-08-24

目录

    /

    返回文章
    返回
    x 关闭 永久关闭