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Article(id=1201096921675952745, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201096916940579367, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2023-1220, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1698595200000, receivedDateStr=2023-10-30, revisedDate=1701014400000, revisedDateStr=2023-11-27, acceptedDate=null, acceptedDateStr=null, onlineDate=1764293421428, onlineDateStr=2025-11-28, pubDate=1712851200000, pubDateStr=2024-04-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1764293421428, onlineIssueDateStr=2025-11-28, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1764293421428, creator=13701087609, updateTime=1764293421428, updator=13701087609, issue=Issue{id=1201096916940579367, tenantId=1146029695717560320, journalId=1189982191388893191, year='2024', volume='59', issue='4', pageStart='789', pageEnd='1100', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1764293420298, creator=13701087609, updateTime=1764293534792, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1201097397242912862, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201096916940579367, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1201097397242912863, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201096916940579367, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=948, endPage=956, ext={EN=ArticleExt(id=1201096923529835158, articleId=1201096921675952745, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=The activity and mechanism of action of a novel Candida albicans biofilm inhibitor IMB-H12, columnId=1190335348761793317, journalTitle=Acta Pharmaceutica Sinica, columnName=Original Articles, runingTitle=null, highlight=null, articleAbstract=

Candida albicans (C. albicans) stands as the primary opportunistic fungal pathogen responsible for fungal infections. The formation of biofilms constitutes a key virulence trait of C. albicans and a pivotal factor in drug resistance. Consequently, the development of antifungal drugs possessing biofilm inhibitory properties holds importance in the treatment of fungal infectious diseases. This study conducted in-depth research of the novel biofilm inhibitor named 1-(cyclopentylamino)-3-(4-(2, 4, 4-trimethylpentan-2-yl)phenoxy)propan-2-ol (IMB-H12). IMB-H12 showed good inhibitory activity on the formation of biofilms and a certain scavenging effect on mature biofilms. Preliminary research on the mechanism of action has found that IMB-H12 can inhibit the transformation from yeast to hyphal phase, inhibit the formation of mycelium, and reduce the adhesion activity and hydrophobicity of Candida albicans. IMB-H12 could also induce changes in the content of cell wall components, downregulate the expression of multiple genes related to adhesion and hyphal formation. Therefore, further research on this compound is expected to discover new lead compounds with antifungal activity.

, correspAuthors=Yan LI, Li-jie YUAN, 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=Dan LI, Xiao-hong ZHU, Cong BIAN, Yuan-juan WEI, Wen-jing SHI, Yan LI, Li-jie YUAN), CN=ArticleExt(id=1201096925870257010, articleId=1201096921675952745, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=新型白念珠菌生物被膜抑制剂IMB-H12的活性和作用机制研究, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

白念珠菌是真菌感染疾病中的主要病原菌, 生物被膜的形成是白念珠菌毒力特征, 同时也是重要的耐药机制, 开发具有生物被膜抑制活性的抗真菌药物具有重要的意义。本研究对前期获得的新型的具有生物被膜抑制活性的化合物1-(cyclopentylamino)-3-(4-(2, 4, 4-trimethylpentan-2-yl)phenoxy)propan-2-ol (简称IMB-H12) 进行了深入的研究。IMB-H12对生物被膜的形成具有良好的抑制活性, 并且对成熟的生物被膜具有一定的清除作用; 初步作用机制研究发现IMB-H12能够抑制酵母-菌丝相的转换、抑制菌丝体的形成, 降低白念珠菌的黏附活性和疏水性; IMB-H12能够诱导生物被膜菌细胞壁成分含量的改变, 下调多个与黏附和菌丝形成相关的基因的表达。因此, 对该化合物的进一步研究, 有望发现新型的具有抗真菌活性的先导化合物。

, correspAuthors=李妍, 袁丽杰, authorNote=null, correspAuthorsNote=
*李妍, E-mail: ;
袁丽杰, E-mail:
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Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China), AuthorCompanyExt(id=1201096927241794464, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096921675952745, companyId=1201096927229211548, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=2.中国医学科学院、北京协和医学院医药生物技术研究所, 抗感染药物研究北京市重点实验室, 北京 100050)])], figs=[ArticleFig(id=1201096932438536455, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096921675952745, language=EN, label=null, caption=null, figureFileSmall=HtfzaLUog6HaSLj1+0EMMg==, figureFileBig=pcgLvbnaXr5T9lME7e6X4Q==, tableContent=null), ArticleFig(id=1201096932543394061, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096921675952745, language=CN, label=Figure 1, caption= Structure of IMB-H12 , figureFileSmall=HtfzaLUog6HaSLj1+0EMMg==, figureFileBig=pcgLvbnaXr5T9lME7e6X4Q==, tableContent=null), ArticleFig(id=1201096932849578274, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096921675952745, language=EN, label=null, caption=null, figureFileSmall=yKNqcljR9ItamMAWo0RtTA==, figureFileBig=S454F3+iBeEOkVmWHFEz8w==, tableContent=null), ArticleFig(id=1201096932954435887, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096921675952745, language=CN, label=Figure 2, caption= Effect of IMB-H12 against <i>Candida albicans</i> (<i>C. albicans</i>) biofilm. <i>C. albicans</i> cells in polystyrene 96-well cell plate were treated with IMB-H12 or DMSO (0.6‰) for different time and biofilm formation was detected by XTT reduction assay. A: Biofilm inhibitory activity of IMB-H12 when IMB-H12 and <i>C. albicans</i> cells were added simultaneously; B: Biofilm inhibitory activity of IMB-H12 when IMB-H12 added after cells adherence; C: Inhibitory activity of IMB-H12 on mature biofilm. <i>n</i> = 3, <span class="mag-xml-overline" style="border-top:1px solid black"><i>x</i></span>±<i>s</i>. <sup>***</sup><i>P</i> < 0.001 <i>vs</i> control , figureFileSmall=yKNqcljR9ItamMAWo0RtTA==, figureFileBig=S454F3+iBeEOkVmWHFEz8w==, tableContent=null), ArticleFig(id=1201096933092847930, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096921675952745, language=EN, label=null, caption=null, figureFileSmall=XyzOZuW0qchpdu64CI5sKA==, figureFileBig=NuMKSkCP7qJrE2hHxXGpNQ==, tableContent=null), ArticleFig(id=1201096933222871368, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096921675952745, language=CN, label=Figure 3, caption= Biofilm inhibitory activity of IMB-H12 with crystal violet staining. The biofilm treated with IMB-H12 or DMSO (0.6‰) for 24 h were stained with 0.1% crystal violet for 20 min and observed by light microscope at a magnification of 10×, and scale bar is 5 μm , figureFileSmall=XyzOZuW0qchpdu64CI5sKA==, figureFileBig=NuMKSkCP7qJrE2hHxXGpNQ==, tableContent=null), ArticleFig(id=1201096933357089105, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096921675952745, language=EN, label=null, caption=null, figureFileSmall=WuMyRg/1HcfyJVsNeQMg5Q==, figureFileBig=iAdvHVhKj6JBXpniSdno6g==, tableContent=null), ArticleFig(id=1201096933520666968, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096921675952745, language=CN, label=Figure 4, caption= IMB-H12 inhibited the transformation of yeast-to-hypha phase of <i>C. albicans</i> cells. <i>C. albicans</i> cells were treated with IMB-H12 or DMSO (0.6‰) for 2, 4, 6 and 8 h, and the morphology of cells were observed by light microscope at a magnification of 40×, scale bar is 1.25 μm , figureFileSmall=WuMyRg/1HcfyJVsNeQMg5Q==, figureFileBig=iAdvHVhKj6JBXpniSdno6g==, tableContent=null), ArticleFig(id=1201096933638107488, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096921675952745, language=EN, label=null, caption=null, figureFileSmall=gTRzxWeVIcNsVY4leWAtvQ==, figureFileBig=WcFBWjUhmAv6SwCi1DBamA==, tableContent=null), ArticleFig(id=1201096933751353698, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096921675952745, language=CN, label=Figure 5, caption= IMB-H12 inhibited the mycelial formation of <i>C. albicans</i> colonies. The working suspension drop (0.5 μL) was transferred to the YEPD solid plate containing IMB-H12 or DMSO (0.6‰) and incubated at 37 ℃ for 7 days. The hyphae of colony were observed with light microscope at a magnification of 10×, scale bar is 5 μm , figureFileSmall=gTRzxWeVIcNsVY4leWAtvQ==, figureFileBig=WcFBWjUhmAv6SwCi1DBamA==, tableContent=null), ArticleFig(id=1201096933898154344, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096921675952745, language=EN, label=null, caption=null, figureFileSmall=6WOpMxIQx923neIG8uts2w==, figureFileBig=5BjqY/FgIrebdWCwyG7LWg==, tableContent=null), ArticleFig(id=1201096934116258162, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096921675952745, language=CN, label=Figure 6, caption= Effect of IMB-H12 against <i>C. albicans</i> biofilm observed by scanning electron microscope (SEM). <i>C. albicans</i> cells in polystyrene cell culture dish were treated with IMB-H12 or DMSO (0.6‰). The biofilm were fixed for 24 h and dehydrated in ethanol solutions. Then, the samples were treated with tert-butanol solutions, coated with gold-palladium and examined on ZEISS-SEM. The magnification was 2 000×, 5 000× and 10 000× , figureFileSmall=6WOpMxIQx923neIG8uts2w==, figureFileBig=5BjqY/FgIrebdWCwyG7LWg==, tableContent=null), ArticleFig(id=1201096934229504379, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096921675952745, language=EN, label=null, caption=null, figureFileSmall=cYexufkr0YvXinA9XXtckQ==, figureFileBig=cMn4Qd+Ijd9pquy1xDBXCQ==, tableContent=null), ArticleFig(id=1201096934388887939, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096921675952745, language=CN, label=Figure 7, caption= IMB-H12 reduced the hydrophobicity and adhesion of <i>C. albicans</i> cells to human oral epithelial cells (HOEC). A: IMB-H12 reduced the hydrophobicity of <i>C. albicans</i> biofilm. The working suspension in 6-well cell culture plates was treated with IMB-H12 or DMSO (0.6‰) for 24 h. The biofilm cells were resuspended in PBS buffer and cell surface hydrophobicity (CSH) was determined by water-hydrocarbon two phase method; B: IMB-H12 inhibited the adhesion of <i>C. albicans</i> cells to HOEC cells. <i>C. albicans</i> cells were treated with IMB-H12 or DMSO (0.6‰) for 12 h at 30 ℃, and then mixed with HOEC cells. After incubating at 37 ℃ for 1 h, the number of <i>C. albicans</i> cells adhering to randomly selected 100 HOEC cells was calculated. <i>n</i> = 3, <span class="mag-xml-overline" style="border-top:1px solid black"><i>x</i></span>±<i>s</i>. <sup>***</sup><i>P</i> < 0.001 <i>vs</i> control , figureFileSmall=cYexufkr0YvXinA9XXtckQ==, figureFileBig=cMn4Qd+Ijd9pquy1xDBXCQ==, tableContent=null), ArticleFig(id=1201096934523105672, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096921675952745, language=EN, label=null, caption=null, figureFileSmall=pYGyzOAHvKHKj6j/JsgDxg==, figureFileBig=pPT8SvdngtUBaCWWA0gD1w==, tableContent=null), ArticleFig(id=1201096934669906319, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096921675952745, language=CN, label=Figure 8, caption= IMB-H12 influenced the polysaccharide of cell wall. <i>C. albicans</i> cells were treated with IMB-H12 or DMSO (0.6‰) for 24 h and stained with calcofluor white (CFW) or ConA-Alexa594. The samples were observed by fluorescence microscope at a magnification of 100×, scale bar is 2.5 μm , figureFileSmall=pYGyzOAHvKHKj6j/JsgDxg==, figureFileBig=pPT8SvdngtUBaCWWA0gD1w==, tableContent=null), ArticleFig(id=1201096934808318361, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096921675952745, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
GeneForward primerReverse primer
18SCGGGCTCTTTGATGATTCCTGCCTTCCTTGGATGTG
CHS1CTGACAAGAGCCAACACTGCCGCCTCTTGATGGTGATGAT
FKS1CGTGAAATTGATCATGCCTGTACAACCCTTCTGGGCTCCAAA
CHT1GCACCAAATACGTCACCATTGCCTGAAATTGACATGTAGCA
ALS3TAATGCTGCTACGTATAATTCCTGAAATTGACATGTAGCA
HWP1TGGTGCTATTACTATTCCGGCAATAATAGCAGCACCGAAG
EFG1TATGCCCCAGCAAACAACTGTTGTTGTCCTGCTGTCTGTC
PLB2TGAACCTTTGGGCGACAACTGCCGCGCTCGTTGTTAA
ECE1GCTGGTATCATTGCTGATATTTCGATGGATTGTTGAACAC
ERG11AAGAATCCCTGAAACCAACAGCAGCAGTATCCCATC
ERG20TTACCCGTGGCATTAGCAATGTATCCCAAGGGAATCAAAATGTCTC
), ArticleFig(id=1201096935009644963, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096921675952745, language=CN, label=Table 1, caption=

Primers used for real-time PCR. 18S: 18S ribosomal-RNA; CHS1: Chitin synthase 1; FKS1: 1, 3-Beta-D-glucan synthase; CHT1 Chitinase 1; ALS3: Agglutinin-like sequence 3; HWP1: Hyphal wall protein 1; EFG1: Enhanced filamentous growth 1; PLB2: Phospholipase B 2; ECE1: Extent of cell elongation 1; ERG11: Sterol 14-demethylase; ERG20: Bifunctional (2E, 6E)-farnesyl diphosphate synthase

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GeneForward primerReverse primer
18SCGGGCTCTTTGATGATTCCTGCCTTCCTTGGATGTG
CHS1CTGACAAGAGCCAACACTGCCGCCTCTTGATGGTGATGAT
FKS1CGTGAAATTGATCATGCCTGTACAACCCTTCTGGGCTCCAAA
CHT1GCACCAAATACGTCACCATTGCCTGAAATTGACATGTAGCA
ALS3TAATGCTGCTACGTATAATTCCTGAAATTGACATGTAGCA
HWP1TGGTGCTATTACTATTCCGGCAATAATAGCAGCACCGAAG
EFG1TATGCCCCAGCAAACAACTGTTGTTGTCCTGCTGTCTGTC
PLB2TGAACCTTTGGGCGACAACTGCCGCGCTCGTTGTTAA
ECE1GCTGGTATCATTGCTGATATTTCGATGGATTGTTGAACAC
ERG11AAGAATCCCTGAAACCAACAGCAGCAGTATCCCATC
ERG20TTACCCGTGGCATTAGCAATGTATCCCAAGGGAATCAAAATGTCTC
), ArticleFig(id=1201096936150495659, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096921675952745, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
GeneRelative fold changeSDDescription and function
CHS11.4890.408Chitin synthase; regulation of synthesis of primary septa in yeast and mycelial phases
FKS11.1170.184Beta-1, 3-glucan synthase subunit
CHT10.7510.110Chitinase, GPI protein, required for normal filamentous growth
ALS30.2180.084Cell adhesins; mycelium-specific correlation
HWP10.0750.022Mycelial cell wall proteins; mycelium-specific genes
EFG10.1300.029Genetic restriction factor 1; regulation of mycelial growth and cell wall genes; adhesion and virulence related
PLB20.4660.036Phospholipase B; tissue degradation, mycelium formation and host invasion, hydrolytic activity
ECE10.0770.112Candida, mycelium-associated regulatory factor, cytolytic peptide toxin essential for mucosal infection
ERG110.3740.026Lanosterol 14-alpha-demethylase; regulation of ergosterol biosynthesis
ERG200.3600.105Farnesian pyrophosphate synthase regulating isoprenoid and sterol biosynthesis
), ArticleFig(id=1201096936301490609, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201096921675952745, language=CN, label=Table 2, caption=

Gene expression changes of biofilm formation related genes

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GeneRelative fold changeSDDescription and function
CHS11.4890.408Chitin synthase; regulation of synthesis of primary septa in yeast and mycelial phases
FKS11.1170.184Beta-1, 3-glucan synthase subunit
CHT10.7510.110Chitinase, GPI protein, required for normal filamentous growth
ALS30.2180.084Cell adhesins; mycelium-specific correlation
HWP10.0750.022Mycelial cell wall proteins; mycelium-specific genes
EFG10.1300.029Genetic restriction factor 1; regulation of mycelial growth and cell wall genes; adhesion and virulence related
PLB20.4660.036Phospholipase B; tissue degradation, mycelium formation and host invasion, hydrolytic activity
ECE10.0770.112Candida, mycelium-associated regulatory factor, cytolytic peptide toxin essential for mucosal infection
ERG110.3740.026Lanosterol 14-alpha-demethylase; regulation of ergosterol biosynthesis
ERG200.3600.105Farnesian pyrophosphate synthase regulating isoprenoid and sterol biosynthesis
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新型白念珠菌生物被膜抑制剂IMB-H12的活性和作用机制研究
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李丹 1 , 朱小红 2 , 卞聪 2 , 魏元娟 2 , 时文静 2 , 李妍 2, * , 袁丽杰 1, *
药学学报 | 研究论文 2024,59(4): 948-956
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药学学报 | 研究论文 2024, 59(4): 948-956
新型白念珠菌生物被膜抑制剂IMB-H12的活性和作用机制研究
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李丹1, 朱小红2, 卞聪2, 魏元娟2, 时文静2, 李妍2, * , 袁丽杰1, *
作者信息
  • 1.华北理工大学基础医学院, 河北省慢性疾病基础医学重点实验室, 唐山市慢性病临床基础研究重点实验室, 河北 唐山 063210
  • 2.中国医学科学院、北京协和医学院医药生物技术研究所, 抗感染药物研究北京市重点实验室, 北京 100050

通讯作者:

*李妍, E-mail: ;
袁丽杰, E-mail:
The activity and mechanism of action of a novel Candida albicans biofilm inhibitor IMB-H12
Dan LI1, Xiao-hong ZHU2, Cong BIAN2, Yuan-juan WEI2, Wen-jing SHI2, Yan LI2, * , Li-jie YUAN1, *
Affiliations
  • 1. Hebei Key Laboratory for Chronic Diseases, Tangshan Key Laboratory for Preclinical and Basic Research on Chronic Diseases, School of Basic Medical Sciences, North China University of Science and Technology, Tangshan 063210, China
  • 2. Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
出版时间: 2024-04-12 doi: 10.16438/j.0513-4870.2023-1220
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摘要
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白念珠菌是真菌感染疾病中的主要病原菌, 生物被膜的形成是白念珠菌毒力特征, 同时也是重要的耐药机制, 开发具有生物被膜抑制活性的抗真菌药物具有重要的意义。本研究对前期获得的新型的具有生物被膜抑制活性的化合物1-(cyclopentylamino)-3-(4-(2, 4, 4-trimethylpentan-2-yl)phenoxy)propan-2-ol (简称IMB-H12) 进行了深入的研究。IMB-H12对生物被膜的形成具有良好的抑制活性, 并且对成熟的生物被膜具有一定的清除作用; 初步作用机制研究发现IMB-H12能够抑制酵母-菌丝相的转换、抑制菌丝体的形成, 降低白念珠菌的黏附活性和疏水性; IMB-H12能够诱导生物被膜菌细胞壁成分含量的改变, 下调多个与黏附和菌丝形成相关的基因的表达。因此, 对该化合物的进一步研究, 有望发现新型的具有抗真菌活性的先导化合物。

白念珠菌  /  生物被膜  /  1-(cyclopentylamino)-3-(4-(2, 4, 4-trimethylpentan-2-yl)phenoxy)propan-2-ol  /  黏附  /  菌丝

Candida albicans (C. albicans) stands as the primary opportunistic fungal pathogen responsible for fungal infections. The formation of biofilms constitutes a key virulence trait of C. albicans and a pivotal factor in drug resistance. Consequently, the development of antifungal drugs possessing biofilm inhibitory properties holds importance in the treatment of fungal infectious diseases. This study conducted in-depth research of the novel biofilm inhibitor named 1-(cyclopentylamino)-3-(4-(2, 4, 4-trimethylpentan-2-yl)phenoxy)propan-2-ol (IMB-H12). IMB-H12 showed good inhibitory activity on the formation of biofilms and a certain scavenging effect on mature biofilms. Preliminary research on the mechanism of action has found that IMB-H12 can inhibit the transformation from yeast to hyphal phase, inhibit the formation of mycelium, and reduce the adhesion activity and hydrophobicity of Candida albicans. IMB-H12 could also induce changes in the content of cell wall components, downregulate the expression of multiple genes related to adhesion and hyphal formation. Therefore, further research on this compound is expected to discover new lead compounds with antifungal activity.

Candida albicans  /  biofilm  /  1-(cyclopentylamino)-3-(4-(2, 4, 4-trimethylpentan-2-yl)phenoxy)propan-2-ol  /  adhere  /  hyphae
李丹, 朱小红, 卞聪, 魏元娟, 时文静, 李妍, 袁丽杰. 新型白念珠菌生物被膜抑制剂IMB-H12的活性和作用机制研究. 药学学报, 2024 , 59 (4) : 948 -956 . DOI: 10.16438/j.0513-4870.2023-1220
Dan LI, Xiao-hong ZHU, Cong BIAN, Yuan-juan WEI, Wen-jing SHI, Yan LI, Li-jie YUAN. The activity and mechanism of action of a novel Candida albicans biofilm inhibitor IMB-H12[J]. Acta Pharmaceutica Sinica, 2024 , 59 (4) : 948 -956 . DOI: 10.16438/j.0513-4870.2023-1220
正文
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随着癌症化疗、器官移植、艾滋病患者的增加和免疫抑制剂的长期广泛使用, 真菌感染, 尤其是深部真菌感染的发生率急剧升高, 侵袭性真菌感染已经成为免疫功能低下患者的主要死亡原因之一[1]。世界卫生组织(WHO) 在2022年首次将真菌列入“优先病原体”名单, 列举了对公共卫生构成最大威胁的19种真菌, 作为真菌感染性疾病中的主要病原菌, 白念珠菌被列在严重级别组[2]。但是目前临床所用抗真菌抗生素种类少, 毒副作用较大, 常用氟康唑也因为大量使用产生了耐药性, 因此新型抗真菌药物的研发具有重要的意义。
白念珠菌通常定植在胃肠道、生殖道、口腔和皮肤。在正常人体中, 白念珠菌通常是无害的。但是当人体免疫功能低下或者局部环境的改变可能会导致白念珠菌过度生长甚至产生侵袭性感染, 生物被膜的形成是白念珠菌的侵袭性感染的毒力特征之一[3]。在此过程中, 酵母相菌首先定植在介质或者宿主组织表面, 以助于组织渗透和宿主免疫的逃避; 然后形成菌丝体, 菌丝体细胞能够分泌多种毒力因子, 造成宿主组织损伤和侵袭性感染, 酵母-菌丝相的转换被认为是白念珠菌关键毒力因素。同时, 生物被膜形成也是白念珠菌产生耐药性的重要原因之一[3-5]。生物被膜是由酵母样细胞、菌丝体和孢子被胞外基质包裹形成的聚集体, 与浮游状态的菌细胞不同, 形成生物被膜的菌细胞难以清除, 对抗真菌药物的耐药性也明显增加。同时, 成熟生物被膜中的细胞游离出来, 散播定植到其他区域, 会形成新的病灶[6]。这些问题给真菌感染的治疗带来了极大的困扰, 具有生物被膜抑制活性的抗真菌药物的发现也受到越来越多的关注。
XTT即2, 3-双(2-甲氧基-4-硝基-5-磺基苯基)-5-[(苯基氨基)羰基]-2H-四唑氢氧化铵是一种四唑盐, 也是线粒体脱氢酶的底物。它可以被呼吸链细胞质中的酶还原成水溶性甲臜。XTT测定法可以高效地测量活细胞中水溶性甲臜的还原从而反映生物被膜中的活细胞量[7]。在前期工作中, 通过XTT方法筛选到化合物1-(cyclopentylamino)-3-(4-(2, 4, 4-trimethylpentan-2-yl)phenoxy)propan-2-ol (IMB-H12) 能够抑制生物被膜的形成, 其结构为图 1所示。目前, 尚未有该化合物对白念珠菌生物被膜抑制活性的报道, 本研究深入评价了该化合物对生物被膜形成和已经形成的生物被膜的抑制活性; 并且通过酵母-菌丝相转换的抑制、菌丝体的形成、疏水性和黏附性的改变以及相关基因的表达等方面的研究, 初步探索了IMB-H12可能的生物被膜抑制作用机制。
材料与方法
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实验菌株  白念珠菌ATCC 10231来自中国医学科学院医药生物技术研究所国家新药(微生物) 筛选室。
实验试剂和培养基  DMSO (D8371)、蛋白胨(P8450)、结晶紫染料(G1063)、NaHCO3 (S5240)、胰蛋白酶-EDTA消化液(20210910) (中国Solarbio公司); 荧光增白剂28 (910090, 美国Sigma公司); RPMI1640 (31800105)、DMEM培养基(8121446)、胎牛血清(2304529)、酵母提取物(LP0021)、葡萄糖(G8150)、ConA-Alexa 594 (C11253) (美国Thermo Fisher Scientific公司); XTT (N812)、3-吗啉基丙磺酸(MOPS, 0670, 美国Amresco公司); 甲萘醌(M813096, 上海麦克林生化科技有限公司); 酵母RNA试剂盒(CoolaberRE781, 北京Coolaber公司); cDNA合成超级混合试剂盒(Hifair® V one-step RT-gDNA digestion SuperMix for qPCR11142ES60, 上海翌圣生物科技公司); 快速通用SYBR绿色大师(04913914001, 瑞士罗氏公司); Cell Counting Kit-8 (CCK-8) (103873, 美国MedChemExpress生物科技公司)。
化合物IMB-H12以20 mg·mL-1溶于DMSO, -20 ℃储存、YPD液体培养基(1%酵母提取物、2%蛋白胨、2%葡萄糖, 115 ℃高压灭菌20 min, 4 ℃保存); XTT工作液(0.5 mg·mL-1 XTT、1 μmol·L-1甲萘醌, -80 ℃储存); RPMI1640培养基(1% RPMI1640, 0.2% NaHCO3、0.165 mol·L-1 MOPS、2%葡萄糖, pH 6.5, 0.2 μm过滤器过滤除菌, 4 ℃保存)。
实验仪器  多功能微孔板检测仪（EnVision2104-0010, 美国PerkinElmer公司）; 倒置显微镜(DM2500倒置)、荧光显微镜(DM2500) (德国徕卡公司); 扫描电镜(Crossbeam340, 德国ZEISS公司); 实时定量热循环仪(FTC-3000, 加拿大Funglyn Biotech Inc公司)。
菌悬液的配置  从4 ℃保存的YPD固体培养板上挑取ATCC 10231单菌落接种到YPD培养液中, 37 ℃震荡培养至对数生长期。使用RPMI1640培养基稀释至2×106 CFU·mL-1, 备用。
XTT方法  190 μL菌悬液加入到96孔细胞培养板中。为了检测IMB-H12对菌黏附过程的影响, 同时加入10 μL RPMI1640稀释的IMB-H12; 为了检测IMB-H12对黏附后菌生物被膜形成的影响, 在加入菌悬液2 h后用PBS轻轻洗掉未黏附菌, 然后按照每孔200 μL加入RPMI1640倍比稀释的IMB-H12; 为了检测化合物对成熟生物被膜的影响, 200 μL菌悬液加入到96孔板中, 37 ℃静置培养24 h形成生物被膜, 用PBS轻轻洗掉未黏附菌, 然后加入RPMI1640稀释的IMB-H12。所有实验组IMB-H12的终浓度为1.56~6.25 μg·mL-1, 以0.6‰ DMSO处理孔为无药对照。96孔板在37 ℃静置培养, 分别在2、12、24和48 h使用PBS轻轻地清洗3次, 去除未黏附菌。然后, 每孔加入100 μL XTT工作液, 避光孵育2 h后测A490。每个浓度设置3个复孔, 实验重复3次。以无药对照组生成率为100%, IMB-H12处理组相对生物被膜生成率(biofilm formation rate/%) 计算公式如下: (A490 IMB-H12/A490 DMSO) × 100%。
结晶紫染色  菌悬液按照每孔4 mL加入到6孔细胞培养板中。加入10 μL RPMI1640倍比稀释的IMB-H12, 使其终浓度为1.56~6.25 μg·mL-1。0.6‰ DMSO处理孔为无药对照。37 ℃静置培养24 h后, 使用PBS轻洗3次以洗去悬浮真菌。倒置沥干, 每孔加1 mL 0.1%结晶紫染液, 避光染色20 min, 弃去孔内染液, 用PBS冲洗3次。倒置沥干, 倒置显微镜×10倍观察。
IMB-H12对白念珠菌酵母-菌丝相转换的影响  菌悬液按照每孔200 μL加入到96孔细胞培养板中。37 ℃静置培养2 h后, PBS轻洗去除未黏附的菌细胞, 然后加入200 μL RPMI1640倍比稀释的IMB-H12, 浓度为1.56~6.25 μg·mL-1, 0.6‰ DMSO处理孔为无药对照。在2、4、6、8 h使用倒置显微镜40倍观察菌的形态变化。
菌落形态  制备含3.13~12.5 μg·mL-1 IMB-H12的固体YPD培养基平板, 接种0.5 μL菌悬液, 0.6‰ DMSO处理孔为无药对照。37 ℃静置培养7天。使用倒置显微镜10倍观察菌落边缘的菌丝形态。
扫描电镜  菌悬液4 mL接种至60 mm细胞培养皿中, 然后加入倍比稀释的IMB-H12, 使其终浓度为0.39~3.13 μg·mL-1, 0.6‰ DMSO处理孔为无药对照。37 ℃静置培养24 h后, 使用PBS冲洗3次以洗去悬浮真菌。加入电镜固定液固定过夜。在一系列乙醇溶液中脱水(30%、50%、70%、90%和100%); 在叔丁醇梯度置换干燥(50%、70%、90%和100%)。离子溅射仪喷金, 扫描电镜随机选取视野拍照。
细胞疏水性(cell surface hydrophobicity, CSH) 的检测  使用碳氢黏附法(microbial adhesion to hydrocarbons, MATH) 测定CSH[8, 9]。菌悬液按照每孔4 mL接种至6孔细胞培养板。加入RPMI1640倍比稀释的IMB-H12, 终浓度为0.78~3.13 μg·mL-1, 0.6‰ DMSO处理孔为无药对照。37 ℃静置培养24 h后, PBS清洗3次去除悬浮细胞。然后PBS冲洗生物被膜成悬液, 检测该悬浮液的A600, 该值为A1。取800 μL上述悬液加入200 μL甲苯, 涡旋2 min, 静置10 min。取下层水相检测A600值为A2。每个浓度设置3个复孔, 实验重复3次。疏水性计算公式如下所示: (1-A2/A1) × 100%。
人口腔上皮细胞(human oral epithelial cells, HOEC) 的培养  冻存细胞自液氮中取出后1 000 r·min-1离心4 min, 去掉上清后细胞重悬于DMEM培养基(10%胎牛血清), 接种于细胞培养瓶中传代1次后, 使用胰酶将细胞消化成单个细胞, 使用RPMI1640培养基调整细胞为105 CFU·mL-1备用。
细胞黏附实验  从4 ℃保存的YPD固体培养板上挑取单菌落接种到YPD培养液中, 37 ℃震荡培养至对数生长期。使用YPD培养菌稀释至1×105 CFU·mL-1, 加入IMB-H12, 使其终浓度为1.56~6.25 μg·mL-1, 以0.6‰ DMSO处理孔为无药对照。30 ℃培养12 h离心去掉上清, 然后使用RPMI1640调整菌浓度为1×107 CFU·mL-1。取0.1 mL细胞和0.1 mL菌悬液混匀, 37 ℃温育1 h, 150 r·min-1离心后PBS洗涤。弃上清, 取沉淀涂片, 随机镜检100个细胞上黏附的菌的数量, 实验重复3次, 菌黏附数量为3次平均数。以无药对照组的菌黏附量为100%, IMB-H12处理组的菌黏附数相对百分率(relative adhesion rate/%) 按照如下公式计算: 相对黏附率% = (菌数IMB-H12/菌数无药对照组) × 100%。
细胞壁染色  菌悬液按照每孔4 mL加入至6孔细胞培养板中, 然后加入IMB-H12, 使其终浓度为1.56~6.25 μg·mL-1, 0.6‰ DMSO处理孔为无药对照。37 ℃静置培养24 h后弃去培养液, 使用PBS轻洗3次以洗去悬浮真菌。加入4%多聚甲醛组织固定液固定30 min后, 用PBS洗涤, 分别进行染色后涂片, 在荧光显微镜下使用100×油镜观察并拍照。100 μg·mL-1荧光增白剂28 (calcofluor white, CFW) 避光染色3 min后, 使用紫外荧光观察; ConA-Alexa 594避光染色15 min后, 使用绿色荧光观察。
实时荧光定量PCR (qRT-PCR)  菌悬液按照每孔4 mL接种至6孔细胞培养板中, 加入IMB-H12使其终浓度为0.78 μg·mL-1, 0.6‰ DMSO处理孔为无药对照。37 ℃静置培养24 h后弃去培养液, 使用PBS轻洗3次以洗去悬浮真菌。1 500 ×g离心5 min收集细胞, 采用RNA试剂盒提取及纯化白念珠菌的RNA, NanoDrop分光光度仪测定RNA浓度。实时荧光定量RT-PCR反应体系如下: DEPC水6 μL, PCR Master Mix-Plus 10 μL, Plus Buffer 2 μL, 上下游引物各1 μL, cDNA 1 μL。反应条件如下: 95 ℃预变性60 s, 95 ℃变性15 s, 60 ℃退火60 s, 40个循环, 72 ℃延伸10 min; 最后65~95 ℃熔解曲线分析判断产物的特异性。内参基因为18S RNA, 目的基因如表 1所示, 基因表达量差异计算方法为2-△△Ct法, 2-ΔΔCt即为待测基因在IMB-H12加药处理组菌株的表达量相较于无药对照组菌株的比值。引物序列见表 1。
白念珠菌MIC测定  按照CLSI (Clinical and Laboratory Standards Institute) 所描述的方法检测IMB-H12对浮游状态的白念珠菌抑制活性, 具体检测方法有所改进。取上述菌悬液每孔190 μL加入到96孔细菌培养板中, 然后每孔加入10 μL RPMI1640倍比稀释的IMB-H12, 使其终浓度为0.78~100 μg·mL-1, 以1% DMSO处理菌作为对照。同时做两性霉素B对照。每个浓度设置3个复孔, 实验重复3次。96孔板在37 ℃静置培养24 h, 以不出现肉眼可见的生长最低浓度为MIC值。
细胞毒性评价  冻存的人正常肝细胞L-02自液氮中取出, 离心收集细胞后重悬于含有20%胎牛血清的DMEM培养基, 接种于细胞培养皿, 37 ℃、5% CO2细胞培养箱中培养, 传代1次。传代后细胞使用胰酶消化, 离心收集细胞后重悬于20%胎牛血清DMEM培养基, 按照每孔5 000个(100 μL) 接种于96孔细胞培养板。细胞生长至对数期后, 吸出培养基, 然后加入DMEM培养基倍比稀释的IMB-H12, 药物浓度为0.39~100 μg·mL-1, 同时做1‰ DMSO无药对照。37 ℃、5% CO2细胞培养箱中培养48 h后, 吸出培养基, PBS轻洗两遍后加入DMEM培养基稀释的CCK-8试剂(1∶10稀释), 每孔100 μL, 无药对照孔中加入不含CCK-8的培养基, 作为空白对照。然后将96孔板放入细胞培养箱中2 h, 酶标仪检测A450。每个浓度设置3个复孔, 实验重复3次。抑制率%=[1-(A450IMB-H12-A450空白) / (A450DMSO-A450空白)]×100%, 使用GraphPad Prism 5处理数据, 拟合计算半数抑制浓度(IC50)。
统计学分析  每组数据均进行3次独立重复实验, 数据表示为mean ± SD, 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 IMB-H12抑制白念珠菌生物被膜的形成
1.1 XTT方法评价化合物对生物被膜的抑制活性
评价IMB-H12对不同时期的生物被膜形成的抑制活性。IMB-H12与白念珠菌同时加入到96孔板中, 分别在2、12、24和48 h检测生物被膜的形成, 观察化合物对黏附和不同生物被膜形成阶段的抑制。结果如图 2A所示, 在2 h时, 相对于无药对照菌, 1.56 μg·mL-1化合物作用下菌黏附到孔中的量明显减少, 形成率为对照菌的21.76% ± 7.22%, 随着浓度的增加, 黏附量呈现浓度依赖性的降低, 在6.25 μg·mL-1时, 形成率仅为5.697% ± 3.25%。同时, IMB-H12能够持续地抑制生物被膜的形成, 与无药对照组相比, 各个检测时间IMB-H12处理组的生物被膜形成率均呈现明显剂量依赖性的下降, 6.25 μg·mL-1时, IMB-H12几乎能够完全抑制生物被膜的形成。为了检测化合物对黏附后的白念珠菌生物被膜形成的抑制活性, 在菌加入2 h后, 洗去未黏附的菌, 再加入IMB-H12。结果如图 2B所示, 与同时加入相同, IMB-H12依旧能够剂量依赖性地抑制生物被膜的形成。已经形成生物被膜的白念珠菌对抗真菌药物具有明显的拮抗作用, 也是白念珠菌耐药机制的重要因素之一。为了评价IMB-H12是否对已经形成生物被膜的菌具有杀伤活性, 将白念珠菌接种到96孔板中24 h形成生物被膜, 然后加入IMB-H12, 结果如图 2C所示, IMB-H12具有一定的剂量依赖性的清除作用, 6.25 μg·mL-1 IMB-H12在12和24 h时, 生物被膜形成率仅为无药对照组的54.79% ± 7.23%和15.42% ± 2.72%。
1.2 结晶紫染色
结晶紫能够与细胞核结合从而将细胞染成蓝色, 结晶紫染色也是生物被膜形成的评价方法之一[10], IMB-H12对生物被膜形成的抑制活性通过该方法进一步评价。如图 3所示, 无药对照菌染色呈现深蓝色, 生物被膜密度很高, 细长的菌丝纵横交错形成致密的网状结构。而1.56 μg·mL-1 IMB-H12处理组的染色和网状结构密度明显降低, 并且随着浓度的增加, 染色和网状结构密度呈现剂量依赖性的降低, 在6.25 μg·mL-1时染色成为点状, 几乎观察不到长菌丝生成。
2 IMB-H12能够抑制白念珠菌的酵母-菌丝相的转换
假菌丝体是白念珠菌生物被膜形成的重要形态变化, 在白念珠菌黏附2 h后, 加入IMB-H12通过光学显微镜观察化合物对白念珠菌形态的影响。如图 4所示, 从2~8 h, 无药对照菌逐渐形成芽管和长菌丝体, 并且进一步增殖形成菌丝体和酵母相细胞缠绕的微菌落。而1.56和3.13 μg·mL-1 IMB-H12处理菌的菌丝体较短, 微菌落的形成也受到抑制, 6.25 μg·mL-1 IMB-H12则能够将菌细胞完全抑制在酵母相。
3 IMB-H12能够抑制菌落菌丝的形成
菌落菌丝的形成也进一步证实了IMB-H12对白念珠菌菌丝形成的抑制活性[11]。如图 5所示, 在不含有IMB-H12的固体培养基上, 培养7天后, 白念珠菌形成的菌落边缘在显微镜下呈现浓密的长菌丝, 而在含有6.25 μg·mL-1 IMB-H12的培养基上, 丝状物明显稀疏和变短, 并且呈现明显的剂量依赖性。
4 IMB-H12影响生物被膜的形态
IMB-H12对生物被膜形态的影响进一步通过扫描电镜进行了观察, 结果如图 6所示, 在无药对照菌中, 生物被膜以致密的菌丝体交联形态存在, 其间夹杂有酵母样菌。而随着IMB-H12浓度的增加, 菌丝体变得疏松, 酵母样细胞明显增多。此外, IMB-H12处理的菌出现明显的皱缩, 菌体表面出现明显损伤。
5 IMB-H12能够降低白念珠菌的疏水性和对细胞的黏附
CSH是白念珠菌重要的毒力因素之一, 对菌在介质上的黏附和生物被膜形成具有重要作用, CSH值越高, 白念珠菌黏附和生物被膜形成的能力越强[12]。对IMB-H12的白念珠菌CSH的抑制活性进行评价, 结果发现IMB-H12能够呈剂量依赖性地下调白念珠菌生物被膜细胞的疏水性。如图 7A所示, 无药对照菌CSH值为57.18% ± 2.20%, 0.78 μg·mL-1 IMB-H12处理菌的疏水性明显下降, 为41.77% ± 1.08%, 在3.13 μg·mL-1时, CSH下降至18.73% ± 4.45%。同时, 进一步应用口腔上皮细胞评价了IMB-H12对白念珠菌黏附的影响[13], 结果如图 7B所示, 与无药对照菌相比, IMB-H12处理12 h后, 随着化合物浓度的增加, 白念珠菌对细胞的黏附显著下降, 相对黏附率分别为80.05% ± 1.69%、70.61% ± 1.46%和38.92% ± 6.51%。
6 IMB-H12影响细胞壁多糖成分
细胞壁是白念珠菌重要的结构, 在细胞形态的维持、宿主识别和免疫识别方面发挥重要的作用, 与白念珠菌黏附、菌丝形成和交联方面密切相关。几丁质、葡聚糖和甘露聚糖是细胞壁重要的组成成分[14], IMB-H12对生物被膜细胞壁的影响通过这些成分的染色进行评价。CFW能够结合在通过β-连接聚合而成的多糖如几丁质和β-葡聚糖, CFW染色发现与无药对照组相比, IMB-H12处理的菌染色明显降低, 尤其是酵母样细胞的母细胞和子细胞的连接处以及子细胞染色降低更为明显。ConA是能够与甘露聚糖结合的蛋白, 使用荧光标记的ConA蛋白可以用来标记甘露聚糖及相关糖蛋白[15]。使用ConA-Alexa 594染色发现IMB-H12处理的菌染色明显增强(图 8)。
7 IMB-H12影响生物被膜形成相关基因的表达
IMB-H12对多个与黏附、菌丝形成和毒力等生物被膜形成的相关调控基因表达的影响通过qRT-PCR进行评价[16]。基因编码蛋白功能描述来自CGD database (http://www.candidagenome.org/; access on 18 February 2021)。相较于对照组, 在0.78 μg·mL-1 IMB-H12处理的生物被膜中, 与黏附、菌丝形成和细胞膜脂质合成相关的多个调控基因的表达明显下降。基因编码蛋白功能描述和变化见表 2。
8 IMB-H12对浮游白念珠菌的抑制活性和细胞毒性
为了评价IMB-12是否是特异性的生物膜抑制剂, 检测了IMB-H12对浮游白念珠菌的抑制活性, 其MIC为12.5 μg·mL-1, 同样条件下两性霉素B的MIC为0.78 μg·mL-1。IMB-H12对L-02细胞的IC50为21.91 ± 1.083 μg·mL-1。
讨论
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鉴于生物被膜形成在白念珠菌毒力和耐药方面的重要作用, 能够抑制生物被膜形成和清除生物被膜中菌细胞的先导物在抗真菌药物研究中受到越来越多的关注[17]。在前期工作中, 本课题组应用XTT方法筛选到的化合物IMB-H12能够抑制生物被膜的形成, 在本研究中进一步对它进行了评价。IMB-H12能够抑制生物被膜的形成, 对成熟的生物被膜在较高的浓度(6.25 μg·mL-1) 下也表现出良好的抑制活性。形态学、菌落菌丝形成和扫描电镜结果显示, IMB-H12能够抑制酵母-菌丝相的转换和菌丝体的形成; IMB-H12能够抑制白念珠菌的黏附功能和降低生物被膜菌细胞的疏水性, 这些结果表明IMB-H12对生物被膜的抑制活性与其抑制黏附和菌丝形成密切相关。细胞壁染色结果显示, IMB-H12处理的菌细胞壁多糖成分明显改变, 甘露聚糖成分在高浓度处理菌中增加, β-连接聚合而成的多糖(如几丁质和β-葡聚糖) 减少, 与黏附和菌丝形成相关的多个基因表达下调, 这些结果初步提示了IMB-H12抑制黏附和菌丝形成的可能机制。
在白念珠菌生物被膜形成过程中, 酵母样菌细胞首先黏附于介质表面(1~4 h), 形成假菌丝相细胞, 然后大量增殖形成微菌落, 微菌落之间进一步通过胞外多糖等介质交联, 菌丝相细胞和酵母相细胞进一步交叉连接, 形成成熟的生物被膜[18]。为了评价IMB-H12是抑制黏附还是抑制后面的菌丝体形成, 在本研究中评价了IMB-H12与菌同时加入和黏附后(2 h) 加入两种情况下IMB-H12的抑制活性, 结果发现, 不管是同时加入还是黏附后加入, 生物被膜的相对形成率仅仅在1.56 μg·mL-1处理12 h时有比较小的差异, 在12 h的其他浓度和其他处理时间, 两种方式的IMB-H12处理组的生物被膜相对形成率并没有明显的差异; 而在后续的机制评价中, 酵母-菌丝相转换受到抑制、疏水性降低、化合物处理后的菌黏附性降低以及菌丝黏附和形成相关的多个基因明显的下降, 这些结果表明IMB-H12对黏附和菌丝体形成的抑制在其抗生物被膜活性中可能均发挥着重要的作用。IMB-H12对于已经形成生物被膜的白念珠菌(24 h) 依然具有较好的杀伤活性, 在6.25 μg·mL-1处理24 h时, 生物被膜形成率下降至15.423% ± 2.727%, 但是与同时或黏附2 h加入时相比, IMB-H12的抑制活性降低, 说明菌丝状态的生物被膜对IMB-H12具有了一定的拮抗。
真菌的细胞壁是白念珠菌维持形态、保持内外平衡和细胞生存的基本结构, 同时在生物被膜形成的黏附和菌丝生长阶段发挥着重要的作用。细胞壁主要成分几丁质、葡聚糖和甘露聚糖也是抗真菌药物研发的重要靶标[19]。在本研究中, IMB-H12对细胞壁的主要成分具有一定的影响作用, 其作用下的CFW染色明显降低表明几丁质或葡聚糖的合成量减少, ConA-Alexa 594染色发现甘露聚糖成分略有增加, 但是仍然需要更加确切的证据来证实, 比如各种糖类具体含量的测定等。在IMB-H12作用下, 与黏附和菌丝形成等多个生物被膜形成的关键调控因子表达量下降, 这与IMB-H12作用下黏附能力下调和酵母-菌丝相转换等表观结果相一致, 但是这仅仅是RNA水平上的结果, 具体蛋白表达水平是否也与此相一致, 哪个靶蛋白在其中发挥关键的作用, 这些尚需要进一步的研究来证实。
为了评价IMB-H12的生物被膜抑制活性是否与其对白念珠菌抑制活性相关, 本研究也考察了同样菌量和培养基条件下IMB-H12对浮游状态的白念珠菌的生长抑制活性, 结果发现其MIC为12.5 μg·mL-1。在低于该浓度时, 白念珠菌的生长与无药对照无明显差异。而在6.25 μg·mL-1或者更低的浓度时, IMB-H12已经能够显著地抑制生物被膜的形成, 同时对成熟的生物被膜有一定的清除作用。这说明IMB-H12对生物被膜的抑制活性具有一定的特异性, 而并非完全与其抗菌活性相关。
目前, 临床上用于治疗侵入性真菌感染的标准药物两性霉素B毒性大, 唑类药物杀菌活性弱, 耐药性严重, 棘白霉素类药物半衰期短、口服生物利用率低也使得这类药物的临床应用受到限制[20-22]。另一方面, 抗真菌药物的研发进展比较缓慢, 自2006年以来, 未有新型的抗真菌药物被批准应用于临床[23, 24]。因此, 新型抗真菌药物的研发依然具有重要的意义。IMB-H12能够抑制白念珠菌生物被膜的形成和清除已经形成的生物被膜, 为新型抗真菌先导物的发现提供了有益的参考。同时, 考虑到IMB-H12对哺乳动物细胞也具有一定的毒性, 与IMB-H12的抗白色念珠菌活性相比没有很大的差异性, 因此其抗白念珠菌活性尚需在动物体内进一步验证, 作用机制也需要进一步的阐明。
作者贡献: 李丹进行了实验研究及数据收集; 卞聪、朱小红、魏元娟是实验参与者; 时文静对语言文字进行修改; 李妍和袁丽杰进行技术指导并修改论文。所有作者都阅读并认可终稿。
利益冲突: 所有作者均声明不存在利益冲突。
基金
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  • 国家自然科学基金资助项目(32141003)
  • 中国医学科学院医学与健康科技创新工程(2021-I2M-1-070)
  • 河北省自然科学基金资助项目(H2021209027)
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参考文献 引证文献
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doi: 10.16438/j.0513-4870.2023-1220
  • 接收时间：2023-10-30
  • 首发时间：2025-11-28
  • 出版时间：2024-04-12
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  • 收稿日期：2023-10-30
  • 修回日期：2023-11-27
基金
国家自然科学基金资助项目(32141003)
中国医学科学院医学与健康科技创新工程(2021-I2M-1-070)
河北省自然科学基金资助项目(H2021209027)
作者信息
    1.华北理工大学基础医学院, 河北省慢性疾病基础医学重点实验室, 唐山市慢性病临床基础研究重点实验室, 河北 唐山 063210
    2.中国医学科学院、北京协和医学院医药生物技术研究所, 抗感染药物研究北京市重点实验室, 北京 100050

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*李妍, E-mail: ;
袁丽杰, 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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