药学学报

近年来结核分枝杆菌外排泵抑制剂研究进展

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郑承鸿 , 王明华 , 王菊仙 ^*

药学学报 | 综述 2023,58(10): 2995-3003

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药学学报 |综述 2023 , 58 (10) : 2995 -3003

近年来结核分枝杆菌外排泵抑制剂研究进展

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郑承鸿, 王明华, 王菊仙^*

作者信息

中国医学科学院、北京协和医学院, 医药生物技术研究所, 北京 100050

通讯作者:

*王菊仙, Tel: 86-10-63131053, E-mail: wangjuxian@imb.pumc.edu.cn

Research progress on efflux pump inhibitors of Mycobacterium tuberculosis in recent years

Cheng-hong ZHENG, Ming-hua WANG, Ju-xian WANG^*

Affiliations

Institute of Medical Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China

出版时间: 2023-10-12 doi: 10.16438/j.0513-4870.2023-0373

文章导航

摘要

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目前, 一线抗结核药物的耐药问题使得对结核病的防治日益困难, 这对全球公共卫生造成了严重威胁。研究表明, 外排泵是导致细菌产生多药耐药和广泛耐药的重要原因之一, 而外排泵抑制剂可以抑制细菌外排抗菌药物, 从而降低细菌耐药性。目前有大量天然产物和化学合成物质被报道具有外排泵抑制活性, 但因毒性和药代动力学性质等原因至今未运用于临床。因此, 本文对近年来报道的结核分枝杆菌外排泵抑制剂的外排泵抑制活性、抗菌活性以及构效关系进行了总结, 为研发活性更好、毒性更小的新型外排泵抑制剂提供参考。

关键词

细菌耐药 / 结核分枝杆菌 / 外排泵 / 外排泵抑制剂 / 抗菌活性 / 构效关系

Abstract

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Currently, the resistance of first-line anti-tuberculosis drugs has made the prevention and treatment of tuberculosis increasingly difficult, posing a serious threat to global public health. Several studies have shown that efflux pumps are one of the important causes for bacteria to develop multi-drug resistance and extremely-drug resistance, and efflux pump inhibitors can inhibit the efflux of antibacterial drugs, thereby reducing bacterial drug resistance. Numerous natural products and synthetic compounds have been reported to possess efflux pump inhibitory activity, but they have not been applied in clinical settings because of their toxicity, pharmacokinetic properties, etc. Therefore, we summarized the efflux pump inhibitory activity, antimicrobial activity, and structure-activity relationships of reported efflux pump inhibitors against Mycobacterium tuberculosis in recent years, providing references for the development of new efflux pump inhibitors with better activity and lower toxicity.

Key words

bacterial resistance / Mycobacterium tuberculosis / efflux pump / efflux pump inhibitor / antibacterial activity / structure-activity relationship

引用本文

郑承鸿, 王明华, 王菊仙. 近年来结核分枝杆菌外排泵抑制剂研究进展. 药学学报, 2023 , 58 (10) : 2995 -3003 . DOI: 10.16438/j.0513-4870.2023-0373

Cheng-hong ZHENG, Ming-hua WANG, Ju-xian WANG. Research progress on efflux pump inhibitors of Mycobacterium tuberculosis in recent years[J]. Acta Pharmaceutica Sinica, 2023 , 58 (10) : 2995 -3003 . DOI: 10.16438/j.0513-4870.2023-0373

正文

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结核病是一种由结核分枝杆菌(Mycobacterium tuberculosis, Mtb)引起的传染性疾病, 对全球公共卫生造成了严重的威胁^[1]。世界卫生组织于2020年发布的数据显示, 仅2019年, 全球共有1 000万人患上活动性肺结核, 其中有140万人死于该疾病^[2]。此外, 抗生素的长期使用与滥用加速了耐药型Mtb的出现和更替, 导致了多药耐药^[3-5]、广泛耐药^{[6, 7]}和完全耐药^[8]结核病的出现, 这给结核病的防治带来了极大的困难。目前, 一线抗结核药物如异烟肼、利福平、吡嗪酰胺、链霉素、乙胺丁醇等均面临着不同程度的耐药问题^[9], 因此寻找新型抗结核药物迫在眉睫。

细菌外排泵(efflux pumps, EPs) 是细菌将胞内物质运输到胞外的转运蛋白, 具有排出不同结构类型化合物的能力^[10-13]。多项研究表明, 细菌EPs的存在是导致多药耐药和广泛耐药的重要原因之一^[14-17], 它们能够结合并排出细菌胞内的抗菌药物, 使其维持在亚致死浓度, 从而有利于产生具有更高耐药性的突变体^[18-20]。根据氨基酸序列的同源性, 与细菌耐药相关的EPs可分为5个超家族^[21], 分别是三磷酸腺苷结合盒超家族、主要易化超家族、小多药耐药超家族、耐药-结节化细胞分化超家族以及多药与毒物外排家族。其中, 三磷酸腺苷结合盒超家族需要三磷酸腺苷水解供能^[22], 而其余四类超家族则利用膜内外质子的浓度差产生的跨膜质子能排出药物^[23]。大量研究发现, Mtb中含有分属于这5个超家族的EPs, 并且主要集中在三磷酸腺苷结合盒超家族和主要易化超家族。因此, EPs可以作为抑制细菌外排抗菌药物的新靶标, 在一定程度上降低细菌的耐药性。

外排泵抑制剂(efflux pump inhibitors, EPIs) 是以EPs为靶标, 通过抑制细菌外排系统来增强共给药物的抗菌活性^[24], 理论上可以降低细菌对抗生素的内在耐药性, 逆转获得性耐药性以及减少新的耐药突变株出现的频率^[10], 为抵御细菌感染和细菌耐药开辟了一条新路径。

近年来, EPIs引起了学者们的广泛关注, 但对EPIs的研究仍处于实验室研究阶段, 至今没有结核分枝杆菌EPIs被批准上市, 也没有进入临床研究阶段的化学实体。氯丙嗪、维拉帕米、羰基氰化物间氯苯腙(carbonyl cyanide m-chlorophenylhydrazone, CCCP)、利血平、生物香豆素A等药物已被证明具有结核分枝杆菌外排泵抑制活性, 但由于其血药浓度、毒性、稳定性、免疫抑制等方面的缺陷至今未应用于临床^{[20, 25-28]}。因此探索新的结核分枝杆菌EPIs具有重要意义。

本文综述了近年来来自天然产物和化学合成的结核分枝杆菌EPIs, 系统总结了这些EPIs的外排泵抑制活性、抗菌活性以及构效关系, 旨在对新型EPIs的设计和改造提供新的研究思路。

1 天然产物类EPIs

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植物来源的天然化合物作为潜在的EPIs可能通过增强分枝杆菌对抗生素的敏感性而成为常规治疗的一种有前途的辅助药物。近年来发现的具有较强结核分枝杆菌外排泵抑制活性的天然产物类EPIs的化学结构见图 1。

1.1 法尼醇

法尼醇(化合物1, 图 1), 又名合金欢醇、里哪醇, 存在于巴西檀木、黄葵子、依兰依兰等植物中。作为一种天然的植物代谢物, 法尼醇通过破坏细菌细胞膜的完整性, 有效地增强抗菌药物对金葡菌和大肠埃希菌的抑制作用^[29-31]。2010年, Jin等^[32]通过棋盘法协同试验、积累试验和外排试验证明法尼醇在耻垢分枝杆菌mc²155中与溴化乙锭具有良好的协同作用(部分抑菌浓度指数为0.375), 对溴化乙锭的外排抑制率约为54%, 高于CCCP (≈ 47%)、利血平(≈ 35%) 和氯丙嗪(≈ 21%), 略低于维拉帕米(≈ 61%), 且外排抑制作用呈浓度依赖性。同时, 法尼醇对耻垢分枝杆菌mc²155具有中等的抗菌活性, 最低抑菌浓度(minimum inhibitory concentration, MIC) 为64 μg·mL^-1, 其抗菌效果优于利血平(MIC = 256 μg·mL^-1) 和维拉帕米(MIC = 300 μg·mL^-1), 但弱于氯丙嗪(MIC = 32 μg·mL^-1) 和CCCP (MIC = 25 μg·mL^-1)。法尼醇和许多其他倍半萜类天然产物具有较高的安全性, 值得对其进行更深入研究。

1.2 胡椒碱

胡椒碱(化合物2, 图 1), 又名胡椒酰胺、胡椒辣碱, 是从黑胡椒中分离得到的天然产物。2010年, Kumar等^[33]发现胡椒碱对Mtb H37Rv和Mtb rif^r (耐利福平突变菌株) 没有抗菌活性, 但可以使利福平和溴化乙锭对Mtb H37Rv的抑制活性分别提高4倍和8倍, 对Mtb rif^r的抑制活性分别提高8倍和32倍以上, 其协同作用强于对照药物利血平。随后, Jin等^[34]报道了胡椒碱对耻垢分枝杆菌mc²155的外排泵抑制活性总体上与利血平相当, 且呈浓度依赖性。Hegeto等^[35]评价了胡椒碱对Mtb H37Rv ATCC27294和9种具有不同耐药谱的临床分离株的外排泵抑制活性, 结果表明其活性与维拉帕米相当, 但对VERO细胞和小鼠单核巨噬细胞具有一定的毒性, 其选择性指数分别为1.46和0.14。

1.3 草豆蔻来源天然产物

2012年, Gröblacher等^[36]从草豆蔻中分离提取出多个天然产物, 其中绝大多数化合物对耻垢分枝杆菌mc²155的抗菌活性较弱(MIC ≥ 64 μg·mL^-1), 外排泵抑制活性与CCCP相当。仅化合物3 (图 1) 的外排泵抑制活性较强, 与氯丙嗪相当, 优于CCCP, 并且与溴化乙锭和利福平具有良好的协同活性(部分抑菌浓度指数分别为0.27和0.28), 使其对耻垢分枝杆菌mc²155的抗菌活性分别提高4倍和4~8倍。

1.4 天堂椒来源天然产物

为了寻找新的潜在EPIs, Gröblacher等^[37]从天堂椒种子中分离出9个姜酮酚和姜酚类似物, 其中化合物4~6 (图 1) 具有良好的溴化乙锭外排抑制活性, 与维拉帕米活性相当。化合物4使溴化乙锭、利福平和异烟肼的抗菌活性提高4~8倍, 化合物6能增强溴化乙锭和利福平的抗菌活性。此外, 3种化合物对耻垢分枝杆菌mc²155均具有中等的抗菌活性(32 μg·mL^-1 ≤ MIC ≤ 64 μg·mL^-1)。初步的构效关系表明: 该类化合物的母核须为与芳香环相连的脂肪族碳链且链的3位或5位至少有一个取代基; 脂肪链的长度和脂肪链上3位或5位的立体构型是影响外排泵抑制活性的重要因素; 脂肪链3位上存在一个羟基或羰基可以显著提高外排泵抑制活性。

1.5 黄酮类天然产物

许多天然黄酮或异黄酮类化合物已被证明具有外排泵抑制活性^{[26, 38]}, 该类天然产物对金色分枝杆菌具有较强的抗菌活性, 对牛分枝杆菌BCG和耻垢分枝杆菌mc²155也表现出一定的抗菌活性^[39]。其中, 化合物7和8 (图 1) 的外排泵抑制活性较强。化合物7能使溴化乙锭和利福平对耻垢分枝杆菌抗菌活性分别提高128倍和4倍, 化合物8使溴化乙锭的抗菌活性提高4倍。在金色分枝杆菌中, 化合物8的外排泵抑制活性最强, 与维拉帕米相当, 强于与氯丙嗪活性相当的化合物7。Solnier等^[39]发现, 含有更多的亲脂性基团对外排泵抑制活性有利, 可能是因为亲脂性基团可以增加对富含脂质的分枝杆菌胞外被膜的亲和力。

1.6 Carvotacetones类天然产物

2020年, Tran等^[40]报道了从戴星草中分离得到的多种carvotacetones类天然产物。其中, 化合物9 (图 1) 对耻垢分枝杆菌mc²115具有一定的抗菌活性(MIC = 32 μg·mL^-1), 同时能使溴化乙锭的抗菌活性提高8倍。该化合物对耻垢分枝杆菌的外排泵抑制活性强于维拉帕米和氯丙嗪, 对金色分枝杆菌的抑制活性与维拉帕米相当, 强于氯丙嗪。

2 化学合成类EPIs

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除了天然产物来源的报道, EPIs在化学设计、合成方面也取得了一定进展, 主要分为苯并杂环类化合物、二氢吡啶和四氢吡啶类化合物、含稠合三环类化合物和其他结构类型的化合物。

2.1 苯并杂环类化合物

Roy等^[41]发现bonducellin (化合物10, 图 2) 可以增加溴化乙锭对耻垢分枝杆菌mc²155的抗菌活性, 其衍生物对耻垢分枝杆菌具有较好的调节活性, 能使溴化乙锭对耻垢分枝杆菌的抑菌效果提高2~8倍, 且外排泵抑制活性呈浓度依赖性。其中化合物11 (图 2) 的外排泵抑制活性最强, 远优于对照药物维拉帕米。单氟取代的化合物12~14 (图 2) 也具有强于维拉帕米的外排泵抑制活性。构效关系表明: (E)-3-苯乙烯基-7-羟基色满-4-酮的主体结构是产生外排泵抑制活性所必需的; 对3-苯乙烯基进行修饰可以增强外排泵抑制活性; 对5位和8位碳原子进行取代可能会减弱外排泵抑制活性。

异黄酮类天然产物鹰嘴豆芽素A (化合物15, 图 2) 是耻垢分枝杆菌的潜在EPI^[38]。Cannalire等^[42]在鹰嘴豆芽素A的结构基础上, 设计合成了一系列3-苯基喹诺酮类化合物。该类化合物虽然对耻垢分枝杆菌抗菌活性较弱, 对鸟分枝杆菌104和2种克拉霉素耐药菌株(104 mc²3和104 mc²4) 没有抗菌活性, 但具有一定的外排泵抑制活性。其中, 化合物16和17 (图 2) 对耻垢分枝杆菌mc²155和鸟分枝杆菌104具有与对照药物维拉帕米相当的外排泵抑制活性, 特别是对2种克拉霉素耐药菌株, 其外排泵抑制活性是维拉帕米的1.5~2倍, 但两者具有一定的毒性。初步构效关系表明: N-1位被氨基烷基链取代时具有较强的外排泵抑制活性; 叔环胺取代的外排泵抑制活性强于分支叔胺或仲胺; 体积较大的疏水性N-苄基取代使抑制活性减弱。

为解决化合物16和17的毒性问题, Felicetti等^[43]报道了一系列6、7位取代的化合物, 遗憾的是, 大部分化合物的细胞毒性强于化合物16。但是, 化合物18 (图 2) 具有更强的外排泵抑制活性, 它能使克拉霉素对鸟分枝杆菌104的抗菌活性和环丙沙星对2种克拉霉素耐药菌株(鸟分枝杆菌104_CLA3和104_CLA4) 的抗菌活性均提高4倍。值得一提的是, 4 μg·mL^-1 (50%细胞死亡的药物浓度的⅙) 的化合物18与0.25 μg·mL^-1 (血清中允许达到的浓度) 的克拉霉素联合使用时, 可以杀死细胞内的细菌并使细菌活性下降80%以上, 杀菌效果是单独使用等浓度克拉霉素时的2倍。

2015年, Machado等^[44]发现2-(4ʹ-丙氧苯) 喹啉类化合物对分枝杆菌的外排泵具有抑制活性。其中化合物19和20 (图 2) 对耻垢分枝杆菌mc²155的外排泵抑制作用较强, 优于氯丙嗪和硫嘧嗪。化合物21和22 (图 2) 仅表现出较弱的抑制作用。但是, 化合物22对耻垢分枝杆菌mc²155具有较强的抗菌活性(MIC = 8 μg·mL^-1), 强于化合物21 (MIC = 16 μg·mL^-1)、化合物19和20 (MIC = 32 μg·mL^-1)。

2022年, Corona等^[45]又报道了4种2-芳基-3-苯氧甲基喹喔啉类化合物23~26 (图 2), 此类化合物对脓肿分枝杆菌无抗菌活性, 但化合物23~25能使阿奇霉素的抗菌活性提高8倍, 化合物26使其提高2倍。对于阿米卡星, 化合物23和26能使其抗菌活性提高2倍。

2.2 二氢吡啶和四氢吡啶类化合物

在早期研究中, 1, 4-二氢吡啶类化合物作为与治疗癌症相关的跨膜外排泵ABCB1的调节剂, 已被证明是金葡菌等细菌的EPIs^[46-48]。1, 4-二氢吡啶类化合物与ABCB1的结合位点与Mtb的外排泵Rv0194表现出超高的同源性, 因此Rv0194可以作为1, 4-二氢吡啶类化合物的潜在靶标^{[49, 50]}。2016年, Lentz等^[51]合成了一系列N-苯基-1, 4-二氢吡啶类化合物。其中, 化合物27 (图 3) 对Mtb H37Rv的生长抑制率可达到30%, 并且具有较强的外排泵抑制活性, 荧光活性比(fluorescence activity ratio, FAR) 为7.3, 优于对照药物维拉帕米(FAR = 1.4)。此外, 0.3 μg·mL^-1的化合物27 (此浓度下对Mtb生长抑制率小于10%) 能使环丙沙星和氯法齐明对Mtb的生长抑制率分别提高了27%和21%, 说明当化合物27在不影响细菌活性的情况下, 能增强两种药物的抗Mtb活性。他们进一步探索了N-苯基上的取代基位置对1, 4-二氢吡啶类化合物外排泵抑制活性的影响^[52], 发现化合物28和29 (图 3) 对rhodamine 123的外排抑制活性最强(FAR分别为52.49和59.76), 远优于维拉帕米(FAR = 4.10) 和tariquidar (FAR = 15.3)。构效关系表明: 4-苯基残基中甲氧基的存在更有利于增强外排泵抑制活性; N-苯基上2位取代的化合物总体上优于4位取代的化合物。

吡啶[2,3-d]嘧啶是喹啉、喹唑啉和吡啶[1, 2-a]嘧啶的生物电子等排体, 具有抗分枝杆菌的潜力^[53-55]。2019年, Agre等^[56]报道了一系列二氢吡啶[2,3-d]嘧啶-4(3H)酮衍生物, 其中化合物30 (图 3) 不仅对Mtb H37Rv具有较强的抗菌活性(MIC = 1.95 µg·mL^-1), 与对照药物乙胺丁醇(MIC = 1 µg·mL^-1) 和链霉素(MIC = 0.78 µg·mL^-1) 活性相当, 还表现出中等的外排泵抑制活性。此外, 化合物30对THP-1细胞系和RAW 264.7细胞系没有细胞毒性, 选择性指数均大于250。

四氢吡啶等结构是质子转移剂, 可成为细菌的潜在EPIs^[57]。2011年, Silva等^[58]通过计算机模拟和体外试验揭示了四氢吡啶衍生物成为大肠埃希菌EPIs的潜力。2019年, Vianna等^[59]报道了四氢吡啶衍生物NUNL02 (化合物31, 图 3) 对分枝杆菌的外排泵抑制活性。溴化乙锭积累试验结果显示, NUNL02对脓肿分枝杆菌ATCC 19997、AT 07和AT 46的外排泵抑制活性强于对照药物维拉帕米。同时, NUNL02可以使阿米卡星对ATCC 19997的抑制活性提高16倍以上, 使环丙沙星对脓肿分枝杆菌AT 52的抑制活性提高4倍, 使克拉霉素对这4种菌株的活性均提高4倍以上, 其调节活性强于维拉帕米。2021年, Halicki等^[60]报道NUNL02对多药耐药菌株Mtb FURG-2具有极强的外排泵抑制活性, 是对照药物维拉帕米的4倍。但是, NUNL02对J774A.1和MCF-7细胞系具有一定的毒性。

2.3 含稠合三环类化合物

各种稠合三环、非稠合三环类化学增敏剂可以使Mtb耐药菌株敏感^{[61, 62]}。Kumar等^[63]将稠合三环类化学增敏剂作为取代基引入各类化合物结构中, 设计并合成了一系列与维拉帕米共价结合的混合EPIs。其中化合物32和33 (图 4) 具有较强的外排泵抑制活性, 可以使利福平和异烟肼对牛分枝杆菌BCG的抗菌活性提高5倍以上, 也能使利福平对Mtb的抗菌活性增强4倍。同时, 化合物32和33对Mtb H37Rv具有较好的抗菌活性, MIC分别为3.17和1.47 µg·mL^-1。另外, 化合物32的细胞毒性很低(20%抑制浓毒大于100 µg·mL^-1), 而化合物33的毒性与维拉帕米相当, IC₂₀在50~100 µg·mL^-1之间。

此外, 他们还设计了一系列异烟肼与稠合三环类化学增敏剂共价连接的化合物^[64]。其中, 化合物34~37 (图 4) 的外排泵抑制活性是对照药物氯丙嗪的1.4倍到1.9倍。化合物34对Mtb H37Rv和抗单药耐药菌株Mtb R5401表现出较强的抑制活性(MIC均为1.0 μmol·L^-1)。而化合物35对Mtb H37Rv的抗菌活性较强(MIC = 0.25 μmol·L^-1), 但对Mtb R5401抑制活性较弱。化合物36和37没有表现出抗菌活性。Kumar等^{[63, 64]}将现有EPIs或抗结核药物与增敏剂结合, 设计出抗菌活性和外排泵抑制活性均较好的混合EPIs。他们的工作为后续EPIs的开发提供了新的思路, 为更多兼顾抗菌活性和外排泵抑制活性的化合物的设计提供了范例。

喹唑啉酮是一类重要的含氮杂环, 是各种天然产物和药物活性分子的核心骨架, 具有多种生物活性^[65-67]。研究表明, 喹唑啉酮衍生物可恢复氯霉素和诺氟沙星的抗菌活性^[68-72]。2018年, Sen等^[73]报道了一系列喹唑啉酮衍生物, 其中化合物38 (图 4) 的外排抑制活性最强, 能使溴化乙锭对耻垢分枝杆菌mc²155的抗菌活性增强8倍, 优于对照药物维拉帕米和CCCP。化合物39 (图 4) 对诺氟沙星的外排抑制活性最强, 优于对照药物维拉帕米和CCCP, 也能使诺氟沙星的抗菌活性增强8倍, 协同活性介于维拉帕米和CCCP之间。初步的构效关系表明: 有氟原子和氯原子取代的衍生物具有更好的活性; 取代基在喹唑啉酮苯环上的衍生物比在吡啶环上的衍生物具有更好的活性; 氟原子取代在喹唑啉酮苯环4位上的衍生物活性最好, 其次是在苯环3位和4位上氯原子取代的衍生物。

2.4 其他结构化合物

苯甲酰腙类化合物属于席夫碱, 具有抗真菌和抗细菌活性^{[74, 75]}。2021年, Sampiron等^[76]报道了一系列苯甲酰腙类化合物。其中, 化合物40和41 (图 5) 对Mtb H37Rv表现出一定的外排泵抑制活性, 但弱于对照药物CCCP。同时, 化合物40和41对Mtb H37Rv具有较好的抗菌活性(MIC均为7.8 μg·mL^-1), 并且对J774.A1巨噬细胞、Vero细胞、HeLa细胞和SBC细胞系无毒性, 选择性指数均大于6。此外, 研究人员发现此类化合物只有在浓度大于500 μg·mL^-1时, 才会引起一半的红细胞裂解。

2022年, Shyam等^[77]报道了具有抗Mtb特异性活性的分枝杆菌生长素类似物42和43 (图 5)。化合物42和43对耻垢分枝杆菌的抗菌活性较弱(MIC均为128 μg·mL^-1), 但外排泵抑制活性较强, 优于对照药物维拉帕米和氯丙嗪。

3 总结与展望

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由于Mtb的独特性质, 抗生素的短期使用无法达到杀灭和控制Mtb的效果, 但长期使用往往产生不良反应, 使一些患者在治疗完成前终止治疗并产生耐药菌株^{[78, 79]}。抗结核药物的耐药性主要归因于Mtb的特定基因的自发突变, 但EPs的存在也是导致一种或多种抗结核药物耐药的重要原因之一。EPIs的使用可以增加细菌胞内药物的有效浓度, 从而更快达到杀菌效果, 降低因突变产生耐药性的概率。目前, 针对EPIs的研究大多数集中在对天然产物的筛选和发现, 但对于Mtb的天然EPIs的发现更多的是从其他细菌的研究中拓展出来的, 如法尼醇、胡椒碱等。随着对结核分枝杆菌EPIs的重视, 越来越多的研究集中在对具有外排泵抑制活性的结构骨架的修饰及其衍生物的设计上, 如苯并杂环类、二氢吡啶类骨架。值得惊喜的是, Kumar等^{[63, 64]}对混合EPIs的开发为该领域的研究提供了思路, 将化学增敏剂与具有外排泵抑制活性的现有药物活性片段或抗菌药物等相连, 是获得兼具良好外排泵抑制活性和抗菌活性的化合物的新途径。

本文综述的报道中, 有较多化合物对分枝杆菌的外排泵抑制活性优于维拉帕米和氯丙嗪, 这表明对结核分枝杆菌EPIs的开发已经具有一定的基础和成绩, 但是目前仍没有进入临床研究阶段的天然产物和化学合成类EPIs, 进一步发现新的具有外排泵抑制活性的结构骨架、提高EPIs的活性、降低潜在毒性仍是今后的重点研究方向。

作者贡献: 郑承鸿负责文献检索和文章撰写; 王明华负责文章内容核对和修改; 王菊仙负责文章选题、写作思路和文章内容审校。

利益冲突: 所有作者声明无任何利益冲突。

基金

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国家自然科学基金资助项目(3214003)

参考文献

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文献

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参考文献引证文献

排序方式：

[1]

Zhang H, Liu X, Xu C, et al. Guiding tuberculosis control through the healthy China initiative 2019-2030[J]. China CDC Wkly, 2020, 2: 948-950.

https://doi.org/10.46234/ccdcw2020.236

[2]

World Health Organization. Global Tuberculosis Report 2019 [R]. Geneva: WHO, 2020.

[3]

Caminero JA. Treatment of multidrug-resistant tuberculosis: evidence and controversies[J]. Int J Tuberc Lung Dis, 2006, 10: 829-837.

[4]

Chan ED, Laurel V, Strand MJ, et al. Treatment and outcome analysis of 205 patients with multidrug-resistant tuberculosis[J]. Am J Respir Crit Care Med, 2004, 169: 1103-1109.

https://doi.org/10.1164/rccm.200308-1159OC

[5]

Eker B, Ortmann J, Migliori GB, et al. Multidrug- and extensively drug-resistant tuberculosis, Germany[J]. Emerg Infect Dis, 2008, 14: 1700-1706.

https://doi.org/10.3201/eid1411.080729

[6]

Migliori GB, Loddenkemper R, Blasi F, et al. 125 years after Robert Koch's discovery of the tubercle bacillus: the new XDR-TB threat. Is "science" enough to tackle the epidemic?[J]. Eur Respir J, 2007, 29: 423-427.

https://doi.org/10.1183/09031936.00001307

[7]

Mitnick CD, Shin SS, Seung KJ, et al. Comprehensive treatment of extensively drug-resistant tuberculosis[J]. N Engl J Med, 2008, 359: 563-574.

https://doi.org/10.1056/NEJMoa0800106

[8]

Velayati AA, Farnia P, Masjedi MR. The totally drug resistant tuberculosis (TDR-TB)[J]. Int J Clin Exp Med, 2013, 6: 307-309.

[9]

Zhang Z, Zhang H, Lin C. Interpretation of the fourth edition of tuberculosis treatment guidelines of WHO[J]. Chin J Clin Electron Ed (中华临床医师杂志电子版), 2014, 8: 4251-4253. https://www.cnki.com.cn/Article/CJFDTOTAL-HFXZ202206008.htm

[10]

Marquez B. Bacterial efflux systems and efflux pumps inhibitors[J]. Biochimie, 2005, 87: 1137-1147.

https://doi.org/10.1016/j.biochi.2005.04.012

[11]

Fluman N, Bibi E. Bacterial multidrug transport through the lens of the major facilitator superfamily[J]. Biochim Biophys Acta, 2009, 1794: 738-747.

https://doi.org/10.1016/j.bbapap.2008.11.020

[12]

Piddock LJ. Multidrug-resistance efflux pumps - not just for resistance[J]. Nat Rev Microbiol, 2006, 4: 629-636.

https://doi.org/10.1038/nrmicro1464

[13]

Ghazaei C. Mycobacterium tuberculosis and lipids: insights into molecular mechanisms from persistence to virulence[J]. J Res Med Sci, 2018, 23: 63.

https://doi.org/10.4103/jrms.JRMS_904_17

[14]

Askun T, Tumen G, Satil F, et al. In vitro activity of methanol extracts of plants used as spices against Mycobacterium tuberculosis and other bacteria[J]. Food Chem, 2009, 116: 289-294.

https://doi.org/10.1016/j.foodchem.2009.02.048

[15]

Machado D, Pires D, Perdigão J, et al. Ion channel blockers as antimicrobial agents, efflux inhibitors, and enhancers of macrophage killing activity against drug resistant Mycobacterium tuberculosis[J]. PLoS One, 2016, 11: e0149326.

https://doi.org/10.1371/journal.pone.0149326

[16]

Demitto Fde O, do Amaral RC, Maltempe FG, et al. In vitro activity of rifampicin and verapamil combination in multidrug-resistant Mycobacterium tuberculosis[J]. PLoS One, 2015, 10: e0116545.

https://doi.org/10.1371/journal.pone.0116545

[17]

Coelho T, Machado D, Couto I, et al. Enhancement of antibiotic activity by efflux inhibitors against multidrug resistant Mycobacterium tuberculosis clinical isolates from Brazil[J]. Front Microbiol, 2015, 6: 330.

[18]

German N, Kaatz GW, Kerns RJ. Synthesis and evaluation of PSSRI-based inhibitors of Staphylococcus aureus multidrug efflux pumps[J]. Bioorg Med Chem Lett, 2008, 18: 1368-1373.

https://doi.org/10.1016/j.bmcl.2008.01.014

[19]

Gupta AK, Chauhan DS, Srivastava K, et al. Estimation of efflux mediated multi-drug resistance and its correlation with expression levels of two major efflux pumps in mycobacteria[J]. J Commun Dis, 2006, 38: 246-254.

[20]

De Rossi E, Aínsa JA, Riccardi G. Role of mycobacterial efflux transporters in drug resistance: an unresolved question[J]. FEMS Microbiol Rev, 2006, 30: 36-52.

https://doi.org/10.1111/j.1574-6976.2005.00002.x

[21]

Blanco P, Hernando-amado S, Reales-calderon JA, et al. Bacterial multidrug efflux pumps: much more than antibiotic resistance determinants[J]. Microorganisms, 2016, 4: 14.

https://doi.org/10.3390/microorganisms4010014

[22]

Verchère A, Broutin I, Picard M. Photo-induced proton gradients for the in vitro investigation of bacterial efflux pumps[J]. Sci Rep, 2012, 2: 306.

https://doi.org/10.1038/srep00306

[23]

Adam Y, Tayer N, Rotem D, et al. The fast release of sticky protons: kinetics of substrate binding and proton release in a multidrug transporter[J]. Proc Natl Acad Sci U S A, 2007, 104: 17989-17994.

https://doi.org/10.1073/pnas.0704425104

[24]

Kapp E, Malan SF, Joubert J, et al. Small molecule efflux pump inhibitors in Mycobacterium tuberculosis: a rational drug design perspective[J]. Mini Rev Med Chem, 2018, 18: 72-86.

[25]

Kaatz GW, Moudgal VV, Seo SM, et al. Phenothiazines and thioxanthenes inhibit multidrug efflux pump activity in Staphylococcus aureus[J]. Antimicrob Agents Chemother, 2003, 47: 719-726.

https://doi.org/10.1128/AAC.47.2.719-726.2003

[26]

Lechner D, Gibbons S, Bucar F. Modulation of isoniazid susceptibility by flavonoids in mycobacterium[J]. Phytochem Lett, 2008, 1: 71-75.

https://doi.org/10.1016/j.phytol.2008.01.002

[27]

Piddock LJ. Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria[J]. Clin Microbiol Rev, 2006, 19: 382-402.

https://doi.org/10.1128/CMR.19.2.382-402.2006

[28]

Gibbons S, Oluwatuyi M, Kaatz GW. A novel inhibitor of multidrug efflux pumps in Staphylococcus aureus[J]. J Antimicrob Chemother, 2003, 51: 13-17.

[29]

Jabra-rizk MA, Meiller TF, James CE, et al. Effect of farnesol on Staphylococcus aureus biofilm formation and antimicrobial susceptibility[J]. Antimicrob Agents Chemother, 2006, 50: 1463-1469.

https://doi.org/10.1128/AAC.50.4.1463-1469.2006

[30]

Brehm-stecher BF, Johnson EA. Sensitization of Staphylococcus aureus and Escherichia coli to antibiotics by the sesquiterpenoids nerolidol, farnesol, bisabolol, and apritone[J]. Antimicrob Agents Chemother, 2003, 47: 3357-3360.

https://doi.org/10.1128/AAC.47.10.3357-3360.2003

[31]

Kuroda M, Nagasaki S, Ohta T. Sesquiterpene farnesol inhibits recycling of the C55 lipid carrier of the murein monomer precursor contributing to increased susceptibility to beta-lactams in methicillin-resistant Staphylococcus aureus[J]. J Antimicrob Chemother, 2007, 59: 425-432.

https://doi.org/10.1093/jac/dkl519

[32]

Jin J, Zhang J, Guo N, et al. Farnesol, a potential efflux pump inhibitor in Mycobacterium smegmatis[J]. Molecules, 2010, 15: 7750-7762.

https://doi.org/10.3390/molecules15117750

[33]

Kumar A, Khan IA, Koul S, et al. Novel structural analogues of piperine as inhibitors of the NorA efflux pump of Staphylococcus aureus[J]. J Antimicrob Chemother, 2008, 61: 1270-1276.

https://doi.org/10.1093/jac/dkn088

[34]

Jin J, Zhang J, Guo N, et al. The plant alkaloid piperine as a potential inhibitor of ethidium bromide efflux in Mycobacterium smegmatis[J]. J Med Microbiol, 2011, 60: 223-229.

https://doi.org/10.1099/jmm.0.025734-0

[35]

Hegeto LA, Caleffi-ferracioli KR, Nakamura-vasconcelos SS, et al. In vitro combinatory activity of piperine and anti-tuberculosis drugs in Mycobacterium tuberculosis[J]. Tuberculosis (Edinb), 2018, 111: 35-40.

https://doi.org/10.1016/j.tube.2018.05.006

[36]

Gröblacher B, Kunert O, Bucar F. Compounds of Alpinia katsumadai as potential efflux inhibitors in Mycobacterium smegmatis[J]. Bioorg Med Chem, 2012, 20: 2701-2706.

https://doi.org/10.1016/j.bmc.2012.02.039

[37]

Gröblacher B, Maier V, Kunert O, et al. Putative mycobacterial efflux inhibitors from the seeds of Aframomum melegueta[J]. J Nat Prod, 2012, 75: 1393-1399.

https://doi.org/10.1021/np300375t

[38]

Lechner D, Gibbons S, Bucar F. Plant phenolic compounds as ethidium bromide efflux inhibitors in Mycobacterium smegmatis[J]. J Antimicrob Chemother, 2008, 62: 345-348.

https://doi.org/10.1093/jac/dkn178

[39]

Solnier J, Martin L, Bhakta S, et al. Flavonoids as novel efflux pump inhibitors and antimicrobials against both environmental and pathogenic intracellular mycobacterial species[J]. Molecules, 2020, 25: 734.

https://doi.org/10.3390/molecules25030734

[40]

Tran HT, Solnier J, Pferschy-wenzig EM, et al. Antimicrobial and efflux pump inhibitory activity of carvotacetones from Sphaeranthus africanus against mycobacteria[J]. Antibiotics (Basel), 2020, 9: 390.

https://doi.org/10.3390/antibiotics9070390

[41]

Roy SK, Kumari N, Gupta S, et al. 7-Hydroxy-(E)-3-phenylmethylene-chroman-4-one analogues as efflux pump inhibitors against Mycobacterium smegmatis mc² 155[J]. Eur J Med Chem, 2013, 66: 499-507.

https://doi.org/10.1016/j.ejmech.2013.06.024

[42]

Cannalire R, Machado D, Felicetti T, et al. Natural isoflavone biochanin A as a template for the design of new and potent 3-phenylquinolone efflux inhibitors against Mycobacterium avium[J]. Eur J Med Chem, 2017, 140: 321-330.

https://doi.org/10.1016/j.ejmech.2017.09.014

[43]

Felicetti T, Machado D, Cannalire R, et al. Modifications on C₆ and C₇ positions of 3-phenylquinolone efflux pump inhibitors led to potent and safe antimycobacterial treatment adjuvants[J]. ACS Infect Dis, 2019, 5: 982-1000.

https://doi.org/10.1021/acsinfecdis.9b00041

[44]

Machado D, Cannalire R, Santos CS, et al. Boosting effect of 2-phenylquinoline efflux inhibitors in combination with macrolides against Mycobacterium smegmatis and Mycobacterium avium[J]. ACS Infect Dis, 2015, 1: 593-603.

https://doi.org/10.1021/acsinfecdis.5b00052

[45]

Corona P, Ibba R, Piras S, et al. Quinoxaline-based efflux pump inhibitors restore drug susceptibility in drug-resistant nontuberculous mycobacteria[J]. Arch Pharm (Weinheim), 2022, 355: e2100492.

https://doi.org/10.1002/ardp.202100492

[46]

Tsuruo T, Iida H, Nojiri M, et al. Circumvention of vincristine and adriamycin resistance in vitro and in vivo by calcium influx blockers[J]. Cancer Res, 1983, 43: 2905-2910.

[47]

Philip PA, Joel S, Monkman SC, et al. A phase Ⅰ study on the reversal of multidrug resistance (MDR) in vivo: nifedipine plus etoposide[J]. Br J Cancer, 1992, 65: 267-270.

https://doi.org/10.1038/bjc.1992.53

[48]

Leitner I, Nemeth J, Feurstein T, et al. The third-generation P-glycoprotein inhibitor tariquidar may overcome bacterial multidrug resistance by increasing intracellular drug concentration[J]. J Antimicrob Chemother, 2011, 66: 834-839.

https://doi.org/10.1093/jac/dkq526

[49]

Jagodinsky JC, Akgun U. Characterizing the binding interactions between P-glycoprotein and eight known cardiovascular transport substrates[J]. Pharmacol Res Perspect, 2015, 3: e00114.

https://doi.org/10.1002/prp2.114

[50]

Loo TW, Clarke DM. Inhibition of oxidative cross-linking between engineered cysteine residues at positions 332 in predicted transmembrane segments (TM) 6 and 975 in predicted TM12 of human P-glycoprotein by drug substrates[J]. J Biol Chem, 1996, 271: 27482-27487.

https://doi.org/10.1074/jbc.271.44.27482

[51]

Lentz F, Hemmer M, Reiling N, et al. Discovery of novel N-phenyl 1, 4-dihydropyridines with a dual mode of antimycobacterial activity[J]. Bioorg Med Chem Lett, 2016, 26: 5896-5898.

https://doi.org/10.1016/j.bmcl.2016.11.010

[52]

Lentz F, Reiling N, Spengler G, et al. Dually acting nonclassical 1, 4-dihydropyridines promote the anti-tuberculosis (Tb) activities of clofazimine[J]. Molecules, 2019, 24: 2873.

https://doi.org/10.3390/molecules24162873

[53]

Shelke RU, Degani MS, Raju A, et al. Fragment discovery for the design of nitrogen heterocycles as Mycobacterium tuberculosis dihydrofolate reductase inhibitors[J]. Arch Pharm (Weinheim), 2016, 349: 602-613.

https://doi.org/10.1002/ardp.201600066

[54]

Jain PP, Degani MS, Raju A, et al. Identification of a novel class of quinoline-oxadiazole hybrids as anti-tuberculosis agents[J]. Bioorg Med Chem Lett, 2016, 26: 645-649.

https://doi.org/10.1016/j.bmcl.2015.11.057

[55]

Pedgaonkar YY, Lele AC, Desai N, et al. Studies on 5-cyanouracils: expedient synthetic protocol for synthesis of novel pyrido[2,3-d]pyrimidine and pyrimido [4, 5-d]pyrimidine analogs with potential pharmacological activity[J]. Int J Pharm Bio Sci, 2014, 5: 422-439.

[56]

Agre N, Degani M, Gupta A, et al. Synthesis and mycobacterial evaluation of 5-substituted-6-acetyl-2-amino-7-methyl-5, 8-dihydropyrido-[2,3-d]pyrimidin-4(3H)-one derivatives[J]. Arch Pharm (Weinheim), 2019, 352: e1900068.

https://doi.org/10.1002/ardp.201900068

[57]

Taylor MD, Badger EW, Steffen RP, et al. 2-(2-Aryl-2-oxoethylidene)-1, 2, 3,4-tetrahydropyridines. Novel isomers of 1, 4-dihydropyridine calcium channel blockers[J]. J Med Chem, 1988, 31: 1659-1664.

https://doi.org/10.1021/jm00403a030

[58]

Silva L Jr, Carrion LL, Von-groll A, et al. In vitro and in silico analysis of the efficiency of tetrahydropyridines as drug efflux inhibitors in Escherichia coli[J]. Int J Antimicrob Agents, 2017, 49: 308-314.

https://doi.org/10.1016/j.ijantimicag.2016.11.024

[59]

Vianna JS, Ramis IB, Bierhals D, et al. Tetrahydropyridine derivative as efflux inhibitor in Mycobacterium abscessus[J]. J Glob Antimicrob Resist, 2019, 17: 296-299.

https://doi.org/10.1016/j.jgar.2018.12.020

[60]

Halicki PCB, Vianna JS, Zanatta N, et al. 2, 2, 2-Trifluoro-1-(1, 4, 5, 6-tetrahydropyridin-3-yl) ethanone derivative as efflux pump inhibitor in Mycobacterium tuberculosis[J]. Bioorg Med Chem Lett, 2021, 42: 128088.

https://doi.org/10.1016/j.bmcl.2021.128088

[61]

Germann UA, Harding MW. Chemosensitizers to overcome and prevent multidrug resistance?[J]. J Natl Cancer Inst, 1995, 87: 1573-1575.

https://doi.org/10.1093/jnci/87.21.1573

[62]

Ch'ng JH, Mok S, Bozdech Z, et al. A whole cell pathway screen reveals seven novel chemosensitizers to combat chloroquine resistant malaria[J]. Sci Rep, 2013, 3: 1734.

https://doi.org/10.1038/srep01734

[63]

Kumar M, Singh K, Naran K, et al. Design, synthesis, and evaluation of novel hybrid efflux pump inhibitors for use against Mycobacterium tuberculosis[J]. ACS Infect Dis, 2016, 2: 714-725.

https://doi.org/10.1021/acsinfecdis.6b00111

[64]

Kumar M, Singh K, Ngwane AH, et al. Reversed isoniazids: design, synthesis and evaluation against Mycobacterium tuberculosis[J]. Bioorg Med Chem, 2018, 26: 833-844.

https://doi.org/10.1016/j.bmc.2017.12.047

[65]

Khan I, Ibrar A, Ahmed W, et al. Synthetic approaches, functionalization and therapeutic potential of quinazoline and quinazolinone skeletons: the advances continue[J]. Eur J Med Chem, 2015, 90: 124-169.

https://doi.org/10.1016/j.ejmech.2014.10.084

[66]

Zhuang Y, Teng X, Wang Y, et al. New quinazolinone alkaloids within rare amino acid residue from coral-associated fungus, aspergillus versicolor LCJ-5-4[J]. Org Lett, 2011, 13: 1130-1133.

https://doi.org/10.1021/ol103164n

[67]

Bouley R, Kumarasiri M, Peng Z, et al. Discovery of antibiotic (E)-3-(3-carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3H)-one[J]. J Am Chem Soc, 2015, 137: 1738-1741.

https://doi.org/10.1021/jacs.5b00056

[68]

Ghisalberti D, Mahamoud A, Chevalier J, et al. Chloroquinolines block antibiotic efflux pumps in antibiotic-resistant Enterobacter aerogenes isolates[J]. Int J Antimicrob Agents, 2006, 27: 565-569.

https://doi.org/10.1016/j.ijantimicag.2006.03.010

[69]

Malléa M, Mahamoud A, Chevalier J, et al. Alkylaminoquinolines inhibit the bacterial antibiotic efflux pump in multidrug-resistant clinical isolates[J]. Biochem J, 2003, 376: 801-805.

https://doi.org/10.1042/bj20030963

[70]

Gallo S, Chevalier J, Mahamoud A, et al. 4-Alkoxy and 4-thioalkoxyquinoline derivatives as chemosensitizers for the chloramphenicol-resistant clinical Enterobacter aerogenes 27 strain[J]. Int J Antimicrob Agents, 2003, 22: 270-273.

https://doi.org/10.1016/S0924-8579(03)00215-2

[71]

Chevalier J, Atifi S, Eyraud A, et al. New pyridoquinoline derivatives as potential inhibitors of the fluoroquinolone efflux pump in resistant Enterobacter aerogenes strains[J]. J Med Chem, 2001, 44: 4023-4026.

https://doi.org/10.1021/jm010911z

[72]

Mahamoud A, Chevalier J, Baitiche M, et al. An alkylaminoquinazoline restores antibiotic activity in Gram-negative resistant isolates[J]. Microbiology (Reading), 2011, 157: 566-571.

https://doi.org/10.1099/mic.0.045716-0

[73]

Sen T, Neog K, Sarma S, et al. Efflux pump inhibition by 11H-pyrido[2, 1-b]quinazolin-11-one analogues in mycobacteria[J]. Bioorg Med Chem, 2018, 26: 4942-4951.

https://doi.org/10.1016/j.bmc.2018.08.034

[74]

Vijaya-raj KK, Narayana B, Ashalatha BV, et al. Synthesis of some bioactive 2-bromo-5-methoxy-N'-[4-(aryl)-1, 3-thiazol-2-yl]benzohydrazide derivatives[J]. Eur J Med Chem, 2007, 42: 425-429.

https://doi.org/10.1016/j.ejmech.2006.09.010

[75]

Wang Z, Zhi F, Wang R, et al. Synthesis, crystal structures and antibacterial activities of benzohydrazone derivatives from 4-diethylaminosalicylaldehyde[J]. J Chil Chem Soc, 2012, 58: 1763-1766.

[76]

Sampiron EG, Costacurta GF, Calsavara LL, et al. In vitro and in silico evaluations of anti-Mycobacterium tuberculosis activity of benzohydrazones compounds[J]. Microb Drug Resist, 2021, 27: 1564-1577.

https://doi.org/10.1089/mdr.2020.0392

[77]

Shyam M, Verma H, Bhattacharje G, et al. Mycobactin analogues with excellent pharmacokinetic profile demonstrate potent antitubercular specific activity and exceptional efflux pump inhibition[J]. J Med Chem, 2022, 65: 234-256.

https://doi.org/10.1021/acs.jmedchem.1c01349

[78]

Laurenzo D, Mousa SA. Mechanisms of drug resistance in Mycobacterium tuberculosis and current status of rapid molecular diagnostic testing[J]. Acta Trop, 2011, 119: 5-10.

https://doi.org/10.1016/j.actatropica.2011.04.008

[79]

Islam MM, Hameed HMA, Mugweru J, et al. Drug resistance mechanisms and novel drug targets for tuberculosis therapy[J]. J Genet Genomics, 2017, 44: 21-37.

https://doi.org/10.1016/j.jgg.2016.10.002

2023年第58卷第10期

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doi: 10.16438/j.0513-4870.2023-0373

接收时间：2023-03-28
首发时间：2025-11-21
出版时间：2023-10-12

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收稿日期：2023-03-28
修回日期：2023-05-22

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国家自然科学基金资助项目(3214003)

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中国医学科学院、北京协和医学院, 医药生物技术研究所, 北京 100050

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*王菊仙, Tel: 86-10-63131053, E-mail: wangjuxian@imb.pumc.edu.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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