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Article(id=1199782969436107406, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1199782966441378761, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2024-0695, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1721404800000, receivedDateStr=2024-07-20, revisedDate=1726675200000, revisedDateStr=2024-09-19, acceptedDate=null, acceptedDateStr=null, onlineDate=1763980150803, onlineDateStr=2025-11-24, pubDate=1733932800000, pubDateStr=2024-12-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1763980150803, onlineIssueDateStr=2025-11-24, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1763980150803, creator=13701087609, updateTime=1763980150803, updator=13701087609, issue=Issue{id=1199782966441378761, tenantId=1146029695717560320, journalId=1189982191388893191, year='2024', volume='59', issue='12', pageStart='3179', pageEnd='3412', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1763980150088, creator=13701087609, updateTime=1764224975369, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1200809838151324146, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1199782966441378761, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1200809838151324147, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1199782966441378761, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=3282, endPage=3290, ext={EN=ArticleExt(id=1199782969784234657, articleId=1199782969436107406, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Antifungal evaluation and mechanism study of ALK inhibitor HG-14-10-04, columnId=null, journalTitle=Acta Pharmaceutica Sinica, columnName=null, runingTitle=null, highlight=null, articleAbstract=

Invasive fungal infections threaten the lives and health of humans, especially immunodeficient patients or hospitalized patients with serious underlying diseases, and impose a heavy economic burden on society. The emergence of drug-resistant fungi, the formation of biofilms, and the limits and side effects of existing antifungal drugs increase the difficulty of clinical treatment, and there is an urgent need for the development of novel antifungal drugs. Therefore, based on previous kinase chemical library antifungal activity screening studies, this paper further investigates the activity of anaplastic lymphoma kinase (ALK) inhibitor 3-[5-chloro-2-({2-methoxy-4-[4-(4-methylpiperazin-1-yl)hexahydropyridin-1-yl]phenyl}amino)pyrimidin-4-yl]-1H-indole (HG-14-10-04, HG) against various fungi and elucidates its mechanism of action. The in vitro antifungal activity of HG was evaluated by micro liquid-dilution method, time-killing curve, mycelium formation and biofilm formation assays. The results showed that HG exhibited inhibitory and even fungicidal effects against sensitive and resistant Candida albicans, Candida krusei, Cryptococcus neoformans, Candida tropicalis, Candida glabrata and Candida parapsilosis (MICs = 8-16 μg·mL-1); HG significantly inhibited the mycelium and biofilm formation, and destroyed the mature biofilm; and it exhibited synergistic antifungal effects with amphotericin B. The antifungal mechanism of HG was investigated by flow cytometry and transmission electron microscopy, etc. Sequencing analysis showed a total of 1 041 differentially expressed genes, of which 666 were up-regulated and 375 were down-regulated. According to the GO functional classification results, the up-regulated genes were mainly involved in ribosome production, oxidation-reduction and other functions, while the down-regulated genes were mainly involved in the synthesis of carbohydrate, glycoproteins, glycolipids and their metabolism, GPI anchor synthesis, and cytoskeleton and other functions. In addition, HG could significantly increase the level of reactive oxygen species (ROS), induce the fungal necrosis, block the cell cycle at the G0/G1 phase, and change the ultrastructure of the fungi, especially the structure of the fungal cell wall. Therefore, the enhanced inhibitory and fungicidal activity of HG may be related to the elevation of ROS, alteration of cellular ultrastructure (especially cell wall structure) and cell cycle arrest at the G0/G1 phase. Further optimization of its structure will provide a basis for the discovery of novel antifungal drugs or lead compounds.

, correspAuthors=Sheng-zheng WANG, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2024 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Wei LIU, Yan-hong LIU, Ping NI, Meng-sha ZHANG, Yi MA, Sheng-zheng WANG), CN=ArticleExt(id=1199782974024676235, articleId=1199782969436107406, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=ALK抑制剂HG-14-10-04的抗真菌活性及其作用机制研究, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

侵袭性真菌感染威胁人类尤其是免疫缺陷患者或者是患有严重潜在疾病的住院患者生命健康, 给社会带来沉重的经济负担。耐药菌的出现、生物被膜的形成以及现有抗真菌药物的有限性和不良反应, 增加了临床真菌感染治疗难度, 亟需开发新型抗真菌药物。因此, 本文基于前期的激酶化合物库抗真菌活性筛选研究, 进一步考察了间变性淋巴瘤激酶(anaplasticlymphoma kinase, ALK) 抑制剂3-[5-氯-2-({2-甲氧基-4-[4-(4-甲基哌嗪-1-基)六氢吡啶-1-基]苯基}氨基)嘧啶-4-基]-1H-吲哚(HG-14-10-04, HG) 对真菌的生长抑制活性及作用机制。通过微量液基稀释法、菌丝形成、生物被膜形成等实验系统评价HG的体外抗真菌活性。结果显示: 化合物HG对敏感和耐药白念珠菌、克柔念珠菌、新生隐球菌、热带念珠菌、光滑念珠菌和近平滑念珠菌均表现真菌生长抑制和杀菌活性(MIC值为8~16 μg·mL-1); HG能明显抑制真菌菌丝和生物被膜的形成, 并破坏成熟生物被膜; 且与两性霉素B合用表现协同抗真菌作用。通过转录组测序技术、流式细胞术、透射电镜等研究了HG的抗真菌机制。测序分析显示差异表达基因共有1 041个, 其中上调的差异基因有666个, 下调的差异基因有375个。根据GO功能分类结果显示: 上调基因主要涉及核糖体生成、氧化还原等功能, 下调基因主要涉及糖类、糖蛋白、糖脂的合成及其代谢, GPI锚合成, 细胞骨架等功能。此外, HG能明显增加真菌内活性氧(reactive oxygen species, ROS) 水平; 诱导细胞坏死; 将细胞周期阻滞于G0/G1期; 改变真菌细胞的超微结构尤其是细胞壁结构。因此, HG对真菌表现较好的生长抑制和杀菌活性, 其机制可能与上调ROS, 改变细胞超微结构尤其是细胞壁结构, 使真菌细胞阻滞于G0/G1期有关, 后期对其进一步的结构优化, 有望为新型抗真菌先导化合物或候选药物的发现提供基础。

, correspAuthors=王胜正, authorNote=null, correspAuthorsNote=
*王胜正, Tel / Fax: 86-29-84776815, E-mail:
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Strain MIC/μg·mL-1
FLC HG
C. albicans SC5314 0.5 16
FLC-resistant C. albicans 103 > 64 16
C. neoformans 32609 1 16
C. krusei ATCC2340 > 64 16
C. parapsilosis ATCC22019 2-4 16
C. glabrata ATCC1182 > 64 16
C. tropicalis 2718 > 64 8
), ArticleFig(id=1200378753365955504, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1199782969436107406, language=CN, label=Table 1, caption=

Minimal inhibit concentration (MIC) of HG against fungi. FLC: Fluconazole

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Strain MIC/μg·mL-1
FLC HG
C. albicans SC5314 0.5 16
FLC-resistant C. albicans 103 > 64 16
C. neoformans 32609 1 16
C. krusei ATCC2340 > 64 16
C. parapsilosis ATCC22019 2-4 16
C. glabrata ATCC1182 > 64 16
C. tropicalis 2718 > 64 8
), ArticleFig(id=1200378753466618804, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1199782969436107406, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Strain Alone MIC/μg·mL-1 Combination MIC/μg·mL-1 FICI Interaction
AmB HG AmB HG
C. albicans SC5314 0.5 16 0.062 5 4 0.25 Synergism
FLC-resistant C. albicans 103 0.5 16 0.125 4 0.5 Synergism
C. krusei ATCC2340 1 16 0.062 5 4 0.313 Synergism
C. neoformans 32609 0.5 16 0.125 0.5 0.281 Synergism
C. tropicalis 2718 1 8 0.125 4 0.625 Addition
C. glabrata ATCC1182 0.5 16 0.062 5 4 0.250 Synergism
C. parapsilosis ATCC22019 0.5 16 0.125 4 0.500 Synergism
), ArticleFig(id=1200378753588253621, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1199782969436107406, language=CN, label=Table 2, caption=

Combination of HG and AmB against various fungi. AmB: Amphotericin B; FICI: Fractional inhibitory concentration index

, figureFileSmall=null, figureFileBig=null, tableContent=
Strain Alone MIC/μg·mL-1 Combination MIC/μg·mL-1 FICI Interaction
AmB HG AmB HG
C. albicans SC5314 0.5 16 0.062 5 4 0.25 Synergism
FLC-resistant C. albicans 103 0.5 16 0.125 4 0.5 Synergism
C. krusei ATCC2340 1 16 0.062 5 4 0.313 Synergism
C. neoformans 32609 0.5 16 0.125 0.5 0.281 Synergism
C. tropicalis 2718 1 8 0.125 4 0.625 Addition
C. glabrata ATCC1182 0.5 16 0.062 5 4 0.250 Synergism
C. parapsilosis ATCC22019 0.5 16 0.125 4 0.500 Synergism
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ALK抑制剂HG-14-10-04的抗真菌活性及其作用机制研究
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刘伟 1 , 刘艳红 1 , 倪萍 1 , 张梦莎 1 , 马怡 1 , 王胜正 2, *
药学学报 | 研究论文 2024,59(12): 3282-3290
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药学学报 | 研究论文 2024, 59(12): 3282-3290
ALK抑制剂HG-14-10-04的抗真菌活性及其作用机制研究
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刘伟1, 刘艳红1, 倪萍1, 张梦莎1, 马怡1, 王胜正2, *
作者信息
  • 1.陕西科技大学食品科学与工程学院 (生物与医药学院), 陕西 西安 710021
  • 2.空军军医大学药学院, 陕西 西安 710032

通讯作者:

*王胜正, Tel / Fax: 86-29-84776815, E-mail:
Antifungal evaluation and mechanism study of ALK inhibitor HG-14-10-04
Wei LIU1, Yan-hong LIU1, Ping NI1, Meng-sha ZHANG1, Yi MA1, Sheng-zheng WANG2, *
Affiliations
  • 1. School of Food Science and Engineering (School of Biological and Pharmaceutical Science), Shaanxi University of Science & Technology, Xi′an 710021, China
  • 2. School of Pharmacy, Fourth Military Medical University, Xi′an 710032, China
出版时间: 2024-12-12 doi: 10.16438/j.0513-4870.2024-0695
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摘要
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侵袭性真菌感染威胁人类尤其是免疫缺陷患者或者是患有严重潜在疾病的住院患者生命健康, 给社会带来沉重的经济负担。耐药菌的出现、生物被膜的形成以及现有抗真菌药物的有限性和不良反应, 增加了临床真菌感染治疗难度, 亟需开发新型抗真菌药物。因此, 本文基于前期的激酶化合物库抗真菌活性筛选研究, 进一步考察了间变性淋巴瘤激酶(anaplasticlymphoma kinase, ALK) 抑制剂3-[5-氯-2-({2-甲氧基-4-[4-(4-甲基哌嗪-1-基)六氢吡啶-1-基]苯基}氨基)嘧啶-4-基]-1H-吲哚(HG-14-10-04, HG) 对真菌的生长抑制活性及作用机制。通过微量液基稀释法、菌丝形成、生物被膜形成等实验系统评价HG的体外抗真菌活性。结果显示: 化合物HG对敏感和耐药白念珠菌、克柔念珠菌、新生隐球菌、热带念珠菌、光滑念珠菌和近平滑念珠菌均表现真菌生长抑制和杀菌活性(MIC值为8~16 μg·mL-1); HG能明显抑制真菌菌丝和生物被膜的形成, 并破坏成熟生物被膜; 且与两性霉素B合用表现协同抗真菌作用。通过转录组测序技术、流式细胞术、透射电镜等研究了HG的抗真菌机制。测序分析显示差异表达基因共有1 041个, 其中上调的差异基因有666个, 下调的差异基因有375个。根据GO功能分类结果显示: 上调基因主要涉及核糖体生成、氧化还原等功能, 下调基因主要涉及糖类、糖蛋白、糖脂的合成及其代谢, GPI锚合成, 细胞骨架等功能。此外, HG能明显增加真菌内活性氧(reactive oxygen species, ROS) 水平; 诱导细胞坏死; 将细胞周期阻滞于G0/G1期; 改变真菌细胞的超微结构尤其是细胞壁结构。因此, HG对真菌表现较好的生长抑制和杀菌活性, 其机制可能与上调ROS, 改变细胞超微结构尤其是细胞壁结构, 使真菌细胞阻滞于G0/G1期有关, 后期对其进一步的结构优化, 有望为新型抗真菌先导化合物或候选药物的发现提供基础。

间变性淋巴瘤激酶抑制剂  /  抗真菌活性  /  生物被膜  /  转录组测序  /  活性氧  /  细胞壁

Invasive fungal infections threaten the lives and health of humans, especially immunodeficient patients or hospitalized patients with serious underlying diseases, and impose a heavy economic burden on society. The emergence of drug-resistant fungi, the formation of biofilms, and the limits and side effects of existing antifungal drugs increase the difficulty of clinical treatment, and there is an urgent need for the development of novel antifungal drugs. Therefore, based on previous kinase chemical library antifungal activity screening studies, this paper further investigates the activity of anaplastic lymphoma kinase (ALK) inhibitor 3-[5-chloro-2-({2-methoxy-4-[4-(4-methylpiperazin-1-yl)hexahydropyridin-1-yl]phenyl}amino)pyrimidin-4-yl]-1H-indole (HG-14-10-04, HG) against various fungi and elucidates its mechanism of action. The in vitro antifungal activity of HG was evaluated by micro liquid-dilution method, time-killing curve, mycelium formation and biofilm formation assays. The results showed that HG exhibited inhibitory and even fungicidal effects against sensitive and resistant Candida albicans, Candida krusei, Cryptococcus neoformans, Candida tropicalis, Candida glabrata and Candida parapsilosis (MICs = 8-16 μg·mL-1); HG significantly inhibited the mycelium and biofilm formation, and destroyed the mature biofilm; and it exhibited synergistic antifungal effects with amphotericin B. The antifungal mechanism of HG was investigated by flow cytometry and transmission electron microscopy, etc. Sequencing analysis showed a total of 1 041 differentially expressed genes, of which 666 were up-regulated and 375 were down-regulated. According to the GO functional classification results, the up-regulated genes were mainly involved in ribosome production, oxidation-reduction and other functions, while the down-regulated genes were mainly involved in the synthesis of carbohydrate, glycoproteins, glycolipids and their metabolism, GPI anchor synthesis, and cytoskeleton and other functions. In addition, HG could significantly increase the level of reactive oxygen species (ROS), induce the fungal necrosis, block the cell cycle at the G0/G1 phase, and change the ultrastructure of the fungi, especially the structure of the fungal cell wall. Therefore, the enhanced inhibitory and fungicidal activity of HG may be related to the elevation of ROS, alteration of cellular ultrastructure (especially cell wall structure) and cell cycle arrest at the G0/G1 phase. Further optimization of its structure will provide a basis for the discovery of novel antifungal drugs or lead compounds.

anaplasticlymphoma kinase inhibitor  /  antifungal activity  /  biofilm  /  transcriptome sequencing  /  reactive oxygen species  /  cell wall
刘伟, 刘艳红, 倪萍, 张梦莎, 马怡, 王胜正. ALK抑制剂HG-14-10-04的抗真菌活性及其作用机制研究. 药学学报, 2024 , 59 (12) : 3282 -3290 . DOI: 10.16438/j.0513-4870.2024-0695
Wei LIU, Yan-hong LIU, Ping NI, Meng-sha ZHANG, Yi MA, Sheng-zheng WANG. Antifungal evaluation and mechanism study of ALK inhibitor HG-14-10-04[J]. Acta Pharmaceutica Sinica, 2024 , 59 (12) : 3282 -3290 . DOI: 10.16438/j.0513-4870.2024-0695
正文
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侵袭性真菌感染是威胁人类尤其是免疫缺陷患者或者是患有严重潜在疾病的住院患者生命健康的主要因素之一, 给社会带来沉重的经济负担[1]。临床常见的可引起侵袭性感染的真菌主要为白念珠菌、烟曲霉菌和新生隐球菌, 分别造成约20%~40%、50%~90%和20%~70%的死亡率[2, 3]。目前, 临床可选用的抗深部真菌感染药物数量比较有限, 按照作用机制主要分为4类: 抑制细胞膜麦角甾醇合成的三唑类如氟康唑、伊曲康唑、伏立康唑、泊沙康唑等; 与细胞膜麦角甾醇结合增加细胞膜通透性的多烯类如两性霉素B及其类似物; 抑制细胞壁β-1, 3-葡聚糖合成的棘白菌素类如卡泊芬净、米卡芬净、阿尼芬净等; 以及抑制核酸合成的5-氟胞嘧啶[4, 5]。各种耐药菌的出现、生物被膜的形成以及现有抗真菌药物的有限性和不良反应, 使得治疗真菌感染尤其是侵袭性真菌感染愈发棘手, 成为临床的一大难题[6-8]。因此, 研发新结构类型、全新作用机制的抗真菌药物是解决该难题的策略之一。
本课题组前期研究通过对激酶化合物库筛选发现间变性淋巴瘤激酶(anaplasticlymphoma kinase, ALK) 抑制剂3-[5-氯-2-({2-甲氧基-4-[4-(4-甲基哌嗪-1-基)六氢吡啶-1-基]苯基}氨基)嘧啶-4-基]-1H-吲哚(HG-14-10-04, HG) 表现出较好的体外抗真菌活性[9]。如图 1所示, 化合物HG对ALK和多种突变表皮生长因子受体(epidermal growth factor receptor, EGFR) 表现强抑制作用, 目前处于临床前研究阶段, 主要用于抗肿瘤药物研发[10, 11]。为验证ALK抑制与抗真菌活性的相关性, 本研究进一步筛选了8个ALK抑制剂的抗真菌作用, 包括NVP-TAE684、brigatinib、belizatinib、ASP3026、ALK-IN-1、MS4078、alectinib及其盐酸盐类化合物, 但在64 μg·mL-1浓度下均未表现明显的抗真菌活性。本研究进一步通过同源性搜寻, 未发现真菌中含有与ALK类似的基因。基于以上研究, 本课题组认为化合物HG具有抗真菌活性的特异性, 其抗真菌活性与其化学结构特征有关, 而与ALK的抑制活性无关。为研究HG的抗真菌活性特点和作用机制, 本文进一步通过微量液基稀释法、时间-杀菌曲线、菌丝形成、生物被膜形成等实验方法系统评价了HG的抗真菌和抑制真菌生物被膜形成活性, 并采用转录组测序技术、流式细胞技术和透射电镜考察了该化合物的抗真菌作用机制。
材料与方法
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实验菌种和试剂
白念珠菌SC5314、临床分离的氟康唑(fluconazole, FLC) 耐药白念珠菌103、标准菌株光滑念珠菌ATCC1182、近平滑念珠菌ATCC22019、克柔念珠菌ATCC2340、热带念珠菌2718、新生隐球菌32609 (光滑念珠菌和克柔念珠菌惠赠于安徽中医药大学汪长中教授, 其余菌株来自长海医院检验科和海军军医大学姜远英教授课题组)。化合物HG (Chemstan公司, CAS号: 1356962-34-9); 氟康唑(Sigma公司); 两性霉素B (上海毕得医药科技有限公司); 活性氧(reactive oxygen species, ROS) 检测试剂盒、细胞凋亡检测试剂盒、细胞周期检测试剂盒(上海碧云天生物技术有限公司); 蜗牛酶(生工生物工程股份有限公司); 二甲基亚砜、碳酸氢钠及氢氧化钠(天津市天力化学试剂有限公司); 蛋白胨(北京奥博星生物技术有限责任公司); 葡萄糖(天津市科密欧化学试剂有限公司); RPMI 1640 (Gibco公司)。
实验仪器
SW-CJ-JFD型洁净工作台(苏州安泰空气技术有限公司); GP-9080型隔水式培养箱、THZ-98C型恒温振荡箱(上海一恒科学仪器有限公司); Varioskan flash全波长多功能读数仪(赛默飞世尔科技有限公司); 流式细胞仪(美国Beckmen公司); 透射电镜JEM-1400 (日本日立公司)。
微量液基稀释法[12]
该实验依据的是美国临床实验室标准化委员会(clinical and laboratory standards institute, CLSI) M27-A3方案。将实验各菌株35或37 ℃, 200 r·min-1振荡培养16 h, 然后用RPMI 1640培养基调整菌浓度至约103 CFU·mL-1, 吹打混匀。取无菌96孔板, 每排1号孔加100 µL RPMI 1640液体培养基作空白对照, 2~11号加入配置好的菌液及受试药物, 且使得各孔的药物终浓度依次为64、32、16、8、4、2、1、0.5、0.25、0.125 μg·mL-1。12号孔只加菌液不加药物作阳性对照。35或37 ℃恒温培养, 培养24或72 h后进行观察记录, 得对应最小抑菌浓度(minimal inhibit concentration, MIC)。MIC值选用记录方法: 当MIC值高于64 μg·mL-1记为“ > 64 μg·mL-1”; 等于或低于最低浓度时均记为“≤ 0.125 μg·mL-1”。上述实验均平行操作两次, 当观察所得MIC值能准确重复或只差一个浓度时视为有效结果, 并取较高浓度为最终确定值, 否则重新实验直到数据符合要求。
棋盘式微量液基稀释法[13]
棋盘式微量稀释法是体外真菌药敏实验的延伸, 将两种药物一起作用于96孔板上, 以二维棋盘的纵横两个方向分别进行二倍的倍比稀释。实验菌株培养、浓度调整同上操作。取无菌96孔板, 每排1号孔作为空白对照, 加入100 μL RPMI 1640液体培养基; 2~11号加入配置好的菌液及两个受试药物, 使得横向各孔的两性霉素B (amphotericin B, AmB) 终浓度依次为16、8、4、2、1、0.5、0.25、0.125、0.062 5、0.03 μg·mL-1; 而纵向各孔HG的终浓度依次为8、4、2、1、0.5、0.25 μg·mL-1。12号孔只加菌液不加药物作阳性对照。放入35或37 ℃培养箱培养, 24和72 h后进行观察记录。
药物联用的效果评价: 评价联合用药的两种药物相互作用方式的主要参数是部分抑菌浓度指数(fractional inhibitory concentration index, FICI)。抑菌浓度分数(FIC) 是每个药物联合抑菌时所需要MIC和单用时MIC的比值, FICI是两种药物FIC之和。当FICI ≤ 0.5时相互作用是协同作用, FICI越小, 协同作用越强; 0.5 < FICI ≤ 1时为相加作用; 1 < FICI ≤ 4时为无关作用; 而当FICI > 4时, 两药则为拮抗作用。
时间-杀菌曲线测定
挑取实验各菌株35 ℃、200 r·min-1振荡培养16 h。离心收集菌体, 磷酸缓冲盐溶液(phosphate buffer saline, PBS) 洗涤, RPMI 1640培养基调整菌浓度至1×105 CFU·mL-1。将菌液分装, 加不同浓度的化合物, 振摇培养, 在0、6、12、24 h时间点, 从各玻璃管分别取样, 按照10、100和1 000倍等不同倍数稀释菌液, 取100 µL菌液涂铺于沙氏琼脂培养基(Sabouraud′s agar, SDA) 平板, 静置培养48 h后, 数克隆数并计算[12]。
菌丝形成实验
挑取白念珠菌克隆振荡培养16 h。离心去上清, PBS清洗3次。用培养基RPMI 1640+10%胎牛血清混匀, 调整菌液至1×106 CFU·mL-1, 取1 mL菌液于6孔板, 加药混匀, 37 ℃静置培养, 4 h后观察并拍照。
生物被膜形成检测
挑取白念珠菌克隆振荡培养16 h。离心收集菌体, PBS洗涤, RPMI 1640培养基调整菌液至1×106 CFU·mL-1。无菌96孔板(美国Corning公司) 中加入菌悬液100 μL, 37 ℃培养90 min后, PBS清洗3次, 再加入RPMI 1640以及含药的培养基, 37 ℃培养24 h后, 弃上清液, PBS清洗3次, 避光加入150 μL XTT (0.5 mg·mL-1)/甲萘醌(1 μmol·L-1) 混合溶液, 37 ℃避光静置孵育3 h, 吸取70 μL上清液至新的普通96孔板中, 用Varioskan flash全波长多功能读数仪于495 nm处测吸光度值(A)。成熟生物被膜的检测: 无菌96孔板(美国Corning公司) 中加入菌悬液100 μL, 37 ℃培养90 min后, PBS洗3次, 再加入新鲜PRMI 1640培养基, 37 ℃培养24 h后, 再用PBS洗3次, 加入新鲜PRMI 1640以及含药的培养基, 后续操作同生物被膜形成检测[14]。生物被膜形成率= 100% × (药物A495 nm-空白孔A495 nm)/(未加药物A495 nm-空白孔A495 nm)[15]。
转录组测序
挑取白念珠菌克隆振荡培养16 h。离心收集菌体, PBS洗涤, RPMI 1640培养基调整菌液至约5×106 CFU·mL-1。加药HG (MIC) 作用6 h, 离心收集菌体, PBS重复清洗3次, 菌沉淀加入液氮, 并干冰保存。送样至诺禾致源生物信息科技有限公司测序分析。转录组数据保存在NCBI的GEO基因表达的综合数据库中, 登录号为GSE274242。
细胞内活性氧实验
挑取白念珠菌克隆振荡培养16 h。离心收集菌体, PBS洗涤, RPMI 1640培养基调整菌液至约1×106 CFU·mL-1。加药HG作用6 h (35 ℃、200 r·min-1培养), 离心收集沉淀, PBS清洗, 离心去上清, 按照细胞ROS检测试剂盒说明书操作, 加入探针2, 7-二氯荧光素二乙酸酯(2', 7'-dichlorodihydrofluorescein diacetate, DCFH2), 在ROS作用下DCFH2转化为具有绿色荧光的2', 7'-二氯荧光素(2', 7'-dichlorofluorescein, DCF), 荧光信号用流式细胞仪检测[16]。
细胞凋亡实验
挑取白念珠菌克隆振荡培养16 h。离心, PBS清洗, RPMI 1640培养基调整菌液至约1×106 CFU·mL-1。加HG后35 ℃、200 r·min-1培养6或16 h, 离心收集菌, PBS清洗, 加入2%蜗牛酶37 ℃孵育1 h, 离心去上清, PBS清洗, 按照细胞凋亡检测试剂盒说明书操作, 用流式细胞仪检测[17]。
细胞周期实验
挑取白念珠菌克隆振荡培养16 h。离心收集菌体, PBS洗涤, RPMI 1640培养基调整菌液至约1×106 CFU·mL-1。加HG后35 ℃、200 r·min-1培养12 h, 离心收集沉淀, PBS清洗, 加入2%蜗牛酶37 ℃孵育1 h, 离心去上清, PBS清洗, 按照细胞周期检测试剂盒说明书操作, 用流式细胞仪检测[17]。
透射电镜实验
挑取白念珠菌克隆振荡培养16 h, 离心收集菌体, PBS洗涤, RPMI 1640培养基调整菌液至约1×106 CFU·mL-1。加HG后, 35 ℃、200 r·min-1培养12 h。离心收集菌体, PBS清洗, 菌沉淀加固定液后置于4 ℃冰箱, 漂洗, 再进行固定、漂洗、梯度脱水、包埋、切片、染色, 透射电镜观察拍照。
统计学方法
采用GraphPad Prism 8.0软件进行数据处理和作图, 结果以x ± s表示, 不同处理组间的比较采用单因素方差分析(one-way ANOVA), P < 0.05表示差异有统计学意义。
结果
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1 HG抗真菌活性研究
1.1 HG对真菌的生长抑制活性
如表 1所示, HG对测试的7种真菌均具有生长抑制活性。其中HG对热带念珠菌2718的MIC值为8 μg·mL-1, 对耐药白念珠菌103、敏感白念珠菌SC5314、新生隐球菌32609、光滑念珠菌ATCC1182、克柔念珠菌ATCC2340和近平滑念珠菌ATCC22019的MIC值为16 μg·mL-1。
由表 2所示, 单用AmB和HG对热带念珠菌2718的MIC值分别为1和8 μg·mL-1, 两药合用后, AmB和HG对热带念珠菌2718的MIC值分别为0.125和4 μg·mL-1, FICI值为0.625, 提示两药合用对热带念珠菌2718表现为相加作用。对另外6株菌(敏感白念珠菌SC5314、耐药白念珠菌103、克柔念珠菌ATCC2340、新生隐球菌32609、光滑念珠菌ATCC1182和近平滑念珠菌ATCC22019), 单用AmB的MIC值范围为0.5~1 μg·mL-1, HG的MIC值范围为8~16 μg·mL-1, 两药联用后, AmB和HG的MIC值分别降至0.062 5~0.125和0.5~4 μg·mL-1, FICI值范围是0.25~0.50, 均≤ 0.5, 这提示: HG与AmB合用后, 对6株菌(敏感白念珠菌和耐药白念珠菌、克柔念珠菌ATCC2340、新生隐球菌32609和近平滑念珠菌ATCC22019) 均具有协同作用。
如图 2所示, 当浓度为MIC值(8或16 μg·mL-1) 的HG作用于多株真菌(敏感或耐药白念珠菌、光滑念珠菌ATCC1182、热带念珠菌2718、克柔念珠菌ATCC2340、近平滑念珠菌ATCC22019) 24 h后, 其存活菌落数与不加药组相比均减少了超过1×103 CFU·mL-1, 尤其对敏感白念珠菌SC5314, 未观察到存活菌落数, 提示在浓度为MIC值的HG对敏感或耐药白念珠菌、光滑念珠菌ATCC1182、热带念珠菌2718、克柔念珠菌ATCC2340、近平滑念珠菌ATCC22019具有很强的杀真菌活性[18]。当浓度为2 MIC值下, HG作用48 h后对测试的6株真菌表现更强的杀真菌活性, 除热带念珠菌2718外, 其余真菌未观察到存活菌落数。在较低浓度(1/2 MIC) 下, HG对近平滑念珠菌ATCC22019和光滑念珠菌ATCC1182仍表现杀真菌活性, 但对敏感或耐药白念珠菌、克柔念珠菌ATCC2340和热带念珠菌2718表现抑制真菌生长活性, 与氟康唑在MIC浓度下相当。以上结果表明, HG在较高的浓度下表现明显的杀真菌活性, 在低浓度下表现抑制真菌活性。
1.2 HG对白念珠菌菌丝形成的影响
如图 3所示, 空白组的白念珠菌形成明显的菌丝, 氟康唑在1 μg·mL-1浓度下, 不能明显抑制菌丝的形成。而白念珠菌经16或32 μg·mL-1 HG处理4 h后, 真菌细胞仍表现酵母形态, 且细胞体积随HG浓度增大而变小。该实验表明化合物HG能够明显抑制白念珠菌菌丝的形成。
1.3 HG对白念珠菌生物被膜的影响
如图 4所示, HG能够抑制生物被膜的形成, 相较于空白对照组, HG处理组的生物被膜形成率呈现剂量依赖性下降, HG在浓度为2 μg·mL-1时, 形成率为73.55% ± 3.21%, 浓度为16 μg·mL-1时, 形成率为33.05% ± 5.82%; HG能够破坏已经形成的生物被膜, 在浓度为4 μg·mL-1时, 成熟生物被膜百分率为81.18% ± 7.89%, 浓度为16 μg·mL-1时, 成熟生物被膜百分率为67.14% ± 8.21%, 与空白组相比均具有显著性差异(P < 0.01)。由此可知, HG能明显抑制白念珠菌生物被膜的形成, 且能损伤成熟生物被膜。
2 HG抗真菌机制研究
2.1 HG对白念珠菌基因表达的影响
如图 5所示, HG作用于白念珠菌6 h后, 测序分析显示, 与空白组相比, 给药组差异表达基因共有1 041个, 其中上调的差异基因有666个, 下调的差异基因有375个。
如图 6所示, 根据GO功能分类结果显示: 上调基因主要涉及核糖体生成(如MPP10、NOP1、TSR1、UTP13、UTP21等基因)、氧化还原(如YHB1、FRE10、ALK2、GDH3等基因) 等功能; 下调基因主要涉及糖类、糖蛋白、糖脂的合成及其代谢(如PMM1、MNN12、MNN1、KTR4、OST1、MNT1等基因)、糖基磷脂酰肌醇(glycosylphosphatidylinositol, GPI) 锚合成(如GPI1基因)、细胞骨架(如ARC19、ARC18、ARC35等基因) 等功能。
2.2 HG对白念珠菌细胞内ROS的影响
如图 7所示, 16和32 μg·mL-1 HG分别作用于白念珠菌6 h后, 44.5% ± 7.1%和76.8% ± 1.6%的细胞显示DCF荧光染色阳性, 与空白组相比呈显著性差异(P < 0.05)。结果表明, HG能够诱导白念珠菌细胞内ROS水平升高。
2.3 HG引起白念珠菌细胞凋亡
由图 8所示, 化合物HG作用白念珠菌6 h后, 能够诱导部分菌发生细胞凋亡, 在HG浓度为16和32 μg·mL-1时, 凋亡细胞(早期凋亡+晚期凋亡) 比例分别为3.8% ± 2.2%和8.1% ± 2.5%。
由图 9所示, 化合物HG作用白念珠菌16 h后, 能够诱导菌发生细胞坏死, 且随着HG浓度的增大, 细胞坏死比例呈剂量依赖性增加。在HG浓度为8、16和32 μg·mL-1时, 细胞坏死比例分别为30.1% ± 12.3%、78.3% ± 6.5% 和88.1% ± 7.2%。
2.4 HG对白念珠菌细胞周期的影响
由图 10所示, 用不同浓度的HG (16或32 μg·mL-1) 作用白念珠菌后, 白念珠菌出现细胞周期阻滞在G0/G1期现象。空白组中白念珠菌细胞周期G0/G1期、S期和G2/M期的细胞百分率分别为39.1% ± 4.8%、31.2% ± 2.4%和29.8% ± 2.5%; 16 μg·mL-1 HG处理组G0/G1期、S期和G2/M期的细胞百分率分别为51.2% ± 9.1%、45.3% ± 10.8%和3.5% ± 1.2%; 而32 μg·mL-1 HG处理组的G0/G1期、S期和G2/M期的细胞百分率分别为55.5% ± 2.3%、37.6% ± 6.5%和8.9% ± 4.3%。
2.5 HG对白念珠菌超微结构的影响
如图 11所示, 空白组的白念珠菌细胞壁和细胞膜完整, 细胞质染色较深。与空白组相比, 经HG作用后白念珠菌细胞壁质地松散、变厚, 细胞膜轮廓不清, 细胞质密度下降, 并见大的囊泡。结果表明, HG可影响白念珠菌的超微结构, 尤其是细胞壁的完整性, 提示HG的抗真菌作用可能与其影响真菌细胞壁的结构有关。
讨论
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为应对侵袭性真菌感染和日益严重的真菌耐药性, 急需研发新结构类型和新作用机制的抗真菌药物。对此, 本研究团队对激酶类化合物库进行了抗真菌活性筛选, 发现ALK抑制剂HG表现较好的体外抗真菌活性。本文系统评价了化合物HG的抗真菌活性, 并对其作用机制进行了初步研究。研究结果发现HG对多种真菌(敏感和耐药白念珠菌、克柔念珠菌、新生隐球菌、热带念珠菌、光滑念珠菌和近平滑念珠菌) 表现出生长抑制或杀真菌作用, 且能明显抑制白念珠菌菌丝和生物被膜的形成, 并损伤成熟被膜。当HG与AmB联用时, 表现出显著的协同抗真菌作用, 明显降低了AmB的MIC值。初步的机制研究表明, HG能增加细胞内ROS水平, 诱导真菌细胞坏死, 将细胞周期阻滞于G0/G1期, 改变真菌细胞的超微结构, 尤其是细胞壁结构。
作为真菌细胞的最外层, 细胞壁不仅是真菌区别于哺乳动物细胞特有的结构, 而且它在真菌的增殖、存活、酵母-菌丝形态转变、生物被膜形成、免疫逃逸、药物敏感性等过程均发挥了重要作用[19, 20]。抑制细胞壁的合成或者改变其组成结构会影响真菌的存活、增殖以及致病能力, 因此细胞壁一直被认为是开发安全、有效抗真菌药物的理想靶标。本研究中, HG作用后的白念珠菌差异表达基因如PMM1、MNN12、MNN1、KTR4/MNT4、OST1、MNT1、GPI1均明显下调, 基因功能分析发现它们参与了细胞壁甘露糖合成以及蛋白的糖基化等过程。如PMM1基因编码磷酸甘露糖酶, 催化N-或者O-连接甘露糖基化反应, 该基因缺失的酿酒酵母菌在37 ℃生长缺陷[21]。MNN1、MNN12、KTR4、MNT4、MNT1基因编码甘露聚糖转移酶, 参与细胞壁甘露聚糖蛋白合成。文献[22]报道MNT1基因缺失后, 白念珠菌的致病力和毒力均明显减弱。GPI1基因编码GPI锚的合成, GPI锚定蛋白是细胞壁的组成成分之一。与转录组学结果相符合的是, 本文进一步通过透射电镜观察HG作用后的白念珠菌, 发现细胞壁超微结构发生明显改变, 中间层变厚。这提示HG可能通过作用细胞壁相关基因, 影响细胞壁的正常结构而发挥抗真菌作用, 包括抑制真菌生长、菌丝和生物被膜形成, 破坏成熟生物被膜, 杀灭真菌。
酵母-菌丝形态转变是白念珠菌的主要毒力特征之一。其菌丝形态在感染过程中起着关键作用, 可以促进组织渗透、侵袭和逃离免疫细胞[23]。本研究发现, HG作用后的白念珠菌差异表达基因如CDC19、ERG3等发生明显下调, 功能分析发现它们发挥丙酮酸激酶和5, 6-甾醇去饱和酶活性, 参与能量代谢和细胞膜麦角甾醇合成。文献[24, 25]报道CDC19、ERG3基因功能缺失后, 白念珠菌菌丝形成能力发生缺陷, 体内毒力下降。本文通过菌丝形成实验也发现HG能明显抑制白念珠菌菌丝形成, 其机制可能与下调CDC19、ERG3等基因相关。
此外, 转录组学结果还发现HG作用后的白念珠菌差异表达基因如YHB1、FRE10、ALK2、GDH3等发生明显上调, 功能分析发现它们参与氧化还原相关功能。如文献[26, 27]报道, YHB1编码NO双加氧酶, 负责细胞内NO的清除和脱毒, 抗真菌药物AmB能明显诱导白念珠菌YHB1的表达, 而AmB也能明显升高细胞内ROS。本文通过流式细胞术检测也发现HG作用后的白念珠菌细胞内ROS明显升高, 这提示升高细胞内ROS水平可能是HG抗真菌的作用机制之一。此外, HG与AmB联用后, 表现出显著的协同抗真菌作用, 这表明HG在应对AmB耐药性方面具有潜在的应用价值。
综上, HG对多种真菌表现生长抑制或杀真菌作用, 能明显抑制菌丝和生物被膜的形成, 损伤成熟生物被膜, 其作用机制可能与影响细胞壁、升高细胞内ROS有关。然而通过细胞毒性实验发现HG对人胚肾成纤维细胞293T的IC50=2.55 μg·mL-1, 因此后期将对其进行化学结构改造、构效关系探索、选择性提升、机制研究, 有望发现新型抗真菌先导化合物或候选药物。
作者贡献: 刘伟、刘艳红、倪萍、张梦莎、马怡负责完成文中实验部分和数据处理; 刘伟负责撰写文章和数据分析; 王胜正指导实验设计和数据分析, 并修改文章。
利益冲突: 本文的研究内容无任何利益冲突。
基金
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  • 国家自然科学基金面上资助项目(82373733)
  • 陕西省重点研发计划国际合作项目(2024GH-YBXM-18)
  • 陕西科技大学博士科研启动基金项目(2016BJ-52)
文献
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2024年第59卷第12期
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doi: 10.16438/j.0513-4870.2024-0695
  • 接收时间：2024-07-20
  • 首发时间：2025-11-24
  • 出版时间：2024-12-12
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  • 收稿日期：2024-07-20
  • 修回日期：2024-09-19
基金
国家自然科学基金面上资助项目(82373733)
陕西省重点研发计划国际合作项目(2024GH-YBXM-18)
陕西科技大学博士科研启动基金项目(2016BJ-52)
作者信息
    1.陕西科技大学食品科学与工程学院 (生物与医药学院), 陕西 西安 710021
    2.空军军医大学药学院, 陕西 西安 710032

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*王胜正, Tel / Fax: 86-29-84776815, E-mail:
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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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