国际口腔医学杂志 ›› 2022, Vol. 49 ›› Issue (5): 511-520.doi: 10.7518/gjkq.2022050

• 口腔微生物专栏 • 上一篇    下一篇

药物联用逆转白色念珠菌唑类耐药机制的研究进展

杨偲睿1,2(),任彪1,彭显1,徐欣1,2()   

  1. 1.口腔疾病研究国家重点实验室;国家口腔疾病临床医学研究中心;四川大学华西口腔医学院 成都 610041
    2.口腔疾病研究国家重点实验室;国家口腔疾病临床医学研究中心;四川大学华西口腔医院牙体牙髓病科 成都 610041
  • 收稿日期:2021-12-12 修回日期:2022-04-15 出版日期:2022-09-01 发布日期:2022-09-16
  • 通讯作者: 徐欣
  • 作者简介:杨偲睿,硕士,Email:2046460187@qq.com
  • 基金资助:
    国家自然科学基金(81771099)

Research progress on drug synergism with fluconazole in fluconazole-resistant Candida albicans

Yang Sirui1,2(),Ren Biao1,Peng Xian1,Xu Xin1,2()   

  1. 1.State Key Laboratory of Oral Diseass & National Clinical Resenrch Center for Oral Di-seases & West China School of Stomatology, Sichuan University, Chengdu 610041, China
    2.State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Dept. of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
  • Received:2021-12-12 Revised:2022-04-15 Online:2022-09-01 Published:2022-09-16
  • Contact: Xin Xu
  • Supported by:
    National Natural Science Foundation of China(81771099)

摘要:

白色念珠菌是侵袭性真菌中最常见的机会致病菌,唑类药物是临床最常用的抗真菌药物之一,长期广泛使用导致耐药性增加。针对抗真菌药物种类的缺乏,药物联用不仅降低单一药物剂量,同时降低药物毒性,已成为当前防治药物耐药研究领域的热点。文章探讨了药物外排、生物膜形成、钙调磷酸酶及热休克蛋白等白色念珠菌常见的耐药机制,对目前联合用药物逆转白色念珠菌唑类耐药机制的研究进展进行综述,并进一步探讨了未来新型抗真菌药物研发的可能靶点。

关键词: 白色念珠菌, 唑类耐药, 外排泵, 生物膜

Abstract:

Candida albicans is the most common opportunistic pathogen in invasive infections. Azoles, especially fluconazole (FLC) is the most extensively used antifungal drug. However, with the increasingly reported drug resistance, combinatory use of other antifungals that synergize with FLC can reduce the dose and toxicity of both drugs. This strategy represents a promising approach to the management of drug-resistance emergence. This article reviews the common mechanisms of drug resistance developed by Candida albicans and discusses the progress of research on the discovery of drug synergism with FLC to provide reference for the development of novel antifungals.

Key words: Candida albicans, azole-resistant, efflux pump, biofilm

中图分类号: 

  • R 782.2

图1

常见药物联用逆转真菌唑类药物耐药途径"

1 Chen CY, Sheng WH, Tien FM, et al. Clinical characteristics and treatment outcomes of pulmonary invasive fungal infection among adult patients with hematological malignancy in a medical centre in Taiwan, 2008-2013[J]. J Microbiol Immunol Infect, 2020, 53(1): 106-114.
2 Blot M, Lanternier F, Lortholary O. Epidemiology of visceral fungal infection in France and in the world[J]. Rev Prat, 2015, 65(10): 1318-1321.
3 Yang CH, He XS, Chen J, et al. Fungal infection in patients after liver transplantation in years 2003 to 2012[J]. Ann Transplant, 2012, 17(4): 59-63.
4 Kamikawa Y, Mori Y, Nagayama T, et al. Frequency of clinically isolated strains of oral Candida species at Kagoshima University Hospital, Japan, and their susceptibility to antifungal drugs in 2006-2007 and 2012-2013[J]. BMC Oral Health, 2014, 14: 14.
5 Bernal-Trevino A, Gonzalez-Amaro AM, Mendez Gonzalez V, et al. Frequency of Candida in root canals of teeth with primary and persistent endodontic infections[J]. Rev Iberoam Micol, 2018, 35(2): 78-82.
6 Akins RA. An update on antifungal targets and mechanisms of resistance in Candida albicans [J]. Med Mycol, 2005, 43(4): 285-318.
7 Seebacher C. Action mechanisms of modern antifungal agents and resulting problems in the management of onychomycosis[J]. Mycoses, 2003, 46(11/12): 506-510.
8 Arendrup MC, Dzajic E, Jensen RH, et al. Epidemiological changes with potential implication for antifungal prescription recommendations for fungaemia: data from a nationwide fungaemia surveillance programme[J]. Clin Microbiol Infect, 2013, 19(8): E343-E353.
9 Sarkar S, Uppuluri P, Pierce CG, et al. In vitro study of sequential fluconazole and caspofungin treatment against Candida albicans biofilms[J]. Antimicrob Agents Chemother, 2014, 58(2): 1183-1186.
10 Longhi C, Santos JP, Morey AT, et al. Combination of fluconazole with silver nanoparticles produced by Fusarium oxysporum improves antifungal effect against planktonic cells and biofilm of drug-resistant Candida albicans [J]. Med Mycol, 2016, 54(4): 428-432.
11 Wei GX, Xu X, Wu CD. In vitro synergism between berberine and miconazole against planktonic and biofilm Candida cultures[J]. Arch Oral Biol, 2011, 56(6): 565-572.
12 Cowen LE, Sanglard D, Howard SJ, et al. Mechanisms of antifungal drug resistance[J]. Cold Spring Harb Perspect Med, 2014, 5(7): a019752.
13 Lohse MB, Gulati M, Johnson AD, et al. Development and regulation of single-and multi-species Candida albicans biofilms[J]. Nat Rev Microbiol, 2018, 16(1): 19-31.
14 Mukherjee PK, Chandra J, Kuhn DA, et al. Mechanism of fluconazole resistance in Candida albicans biofilms: phase-specific role of efflux pumps and membrane sterols[J]. Infect Immun, 2003, 71(8): 4333-4340.
15 Ghannoum M, Roilides E, Katragkou A, et al. The role of echinocandins in Candida biofilm-related vas-cular catheter infections: in vitro and in vivo model systems[J]. Clin Infect Dis, 2015, 61(): S618-S621.
16 Tsui C, Kong EF, Jabra-Rizk MA. Pathogenesis of Candida albicans biofilm[J]. Pathog Dis, 2016, 74(4): ftw018.
17 Taff HT, Mitchell KF, Edward JA, et al. Mechanisms of Candida biofilm drug resistance[J]. Future Microbiol, 2013, 8(10): 1325-1337.
18 Vediyappan G, Rossignol T, D’Enfert C. Interaction of Candida albicans biofilms with antifungals: transcriptional response and binding of antifungals to beta-glucans[J]. Antimicrob Agents Chemother, 2010, 54(5): 2096-2111.
19 Nobile CJ, Johnson AD. Candida albicans biofilms and human disease[J]. Annu Rev Microbiol, 2015, 69: 71-92.
20 Nett J, Lincoln L, Marchillo K, et al. Putative role of beta-1,3 glucans in Candida albicans biofilm resistance[J]. Antimicrob Agents Chemother, 2007, 51(2): 510-520.
21 Wachtler B, Wilson D, Haedicke K, et al. From attachment to damage: defined genes of Candida albicans mediate adhesion, invasion and damage during interaction with oral epithelial cells[J]. PLoS One, 2011, 6(2): e17046.
22 Liu Y, Filler SG. Candida albicans Als3, a multifunctional adhesin and invasion[J]. Eukaryot Cell, 2011, 10(2): 168-173.
23 Lu Y, Zhou Z, Mo L, et al. Fluphenazine antagonizes with fluconazole but synergizes with amphotericin B in the treatment of candidiasis[J]. Appl Microbiol Biotechnol, 2019, 103(16): 6701-6709.
24 Coste AT, Karababa M, Ischer F, et al. TAC1, transcriptional activator of CDR genes, is a new transcription factor involved in the regulation of Candida albicans ABC transporters CDR1 and CDR2[J]. Eukaryot Cell, 2004, 3(6): 1639-1652.
25 Del Sorbo G, Schoonbeek HJ, De Waard MA. Fungal transporters involved in efflux of natural toxic compounds and fungicides[J]. Fungal Genet Biol, 2000, 30(1): 1-15.
26 Prasad R, Rawal MK. Efflux pump proteins in antifungal resistance[J]. Front Pharmacol, 2014, 5: 202.
27 Wirsching S, Michel S, Morschhauser J. Targeted gene disruption in Candida albicans wild-type strai-ns: the role of the MDR1 gene in fluconazole resistance of clinical Candida albicans isolates[J]. Mol Microbiol, 2000, 36(4): 856-865.
28 Hemenway CS, Heitman J. Calcineurin. Structure, function, and inhibition[J]. Cell Biochem Biophys, 1999, 30(1): 115-151.
29 Liu S, Hou Y, Liu W, et al. Components of the calcium-calcineurin signaling pathway in fungal cells and their potential as antifungal targets[J]. Eukaryot Cell, 2015, 14(4): 324-334.
30 Blankenship JR, Wormley FL, Boyce MK, et al. Calcineurin is essential for Candida albicans survival in serum and virulence[J]. Eukaryot Cell, 2003, 2(3): 422-430.
31 Jia W, Zhang H, Li C, et al. The calcineruin inhibitor cyclosporine a synergistically enhances the susceptibility of Candida albicans biofilms to fluconazole by multiple mechanisms[J]. BMC Microbiol, 2016, 16(1): 113.
32 Pratt WB, Toft DO. Regulation of signaling protein function and trafficking by the hsp90/hsp70-based chaperone machinery[J]. Exp Biol Med (Maywood), 2003, 228(2): 111-133.
33 Cowen LE, Carpenter AE, Matangkasombut O, et al. Genetic architecture of Hsp90-dependent drug resistance[J]. Eukaryot Cell, 2006, 5(12): 2184-2188.
34 Cowen LE, Lindquist S. Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi[J]. Science, 2005, 309(5744): 2185-2189.
35 Li X, Robbins N, O’Meara TR, et al. Extensive functional redundancy in the regulation of Candida albicans drug resistance and morphogenesis by lysine deacetylases Hos2, Hda1, Rpd3 and Rpd31[J]. Mol Microbiol, 2017, 103(4): 635-656.
36 Akins RA. An update on antifungal targets and mechanisms of resistance in Candida albicans [J]. Med Mycol, 2005, 43(4): 285-318.
37 Hoot SJ, Smith AR, Brown RP, et al. An A643V amino acid substitution in Upc2p contributes to azole resistance in well-characterized clinical isolates of Candida albicans [J]. Antimicrob Agents Chemother, 2011, 55(2): 940-942.
38 Lohberger A, Coste AT, Sanglard D. Distinct roles of Candida albicans drug resistance transcription factors TAC1, MRR1, and UPC2 in virulence[J]. Eukaryot Cell, 2014, 13(1): 127-142.
39 Vasicek EM, Berkow EL, Flowers SA, et al. UPC2 is universally essential for azole antifungal resistance in Candida albicans [J]. Eukaryotic Cell, 2014, 13(7): 933-946.
40 Oliveira-Carvalho V, Del Negro GMB. Is the S405F mutation in Candida albicans ERG11 gene sufficient to confer resistance to fluconazole[J]. J Mycol Med, 2014, 24(3): 241-242.
41 Ying Y, Zhao YJ, Hu XF, et al. In vitro fluconazole susceptibility of 1 903 clinical isolates of Candida albicans and the identification of ERG11 mutations[J]. Microb Drug Resist, 2013, 19(4): 266-273.
42 Liu S, Yue L, Gu W, et al. Synergistic effect of fluconazole and calcium channel blockers against resistant candida albicans[J]. PLoS One, 2016, 11(3): e0150859.
43 Liu S, Hou Y, Chen X, et al. Combination of fluconazole with non-antifungal agents: a promising approach to cope with resistant Candida albicans infections and insight into new antifungal agent discovery[J]. Int J Antimicrob Agents, 2014, 43(5): 395-402.
44 Holmes AR, Cardno TS, Strouse JJ, et al. Targeting efflux pumps to overcome antifungal drug resistance[J]. Future Med Chem, 2016, 8(12): 1485-1501.
45 Liu RH, Shang ZC, Li TX, et al. In vitro antibiofilm activity of eucarobustol E against Candida albicans [J]. Antimicrob Agents Chemother, 2017, 61(8): e02707-e02716.
46 Xu J, Liu R, Sun F, et al. Eucalyptal D enhances the antifungal effect of fluconazole on fluconazole-resistant Candida albicans by competitively inhibiting efflux pump[J]. Front Cell Infect Microbiol, 2019, 9: 211.
47 Yang DL, Hu YL, Yin ZX, et al. Cis-2-dodecenoic acid mediates its synergistic effect with triazoles by interfering with efflux pumps in fluconazole-resistant Candida albicans [J]. Biomed Environ Sci, 2019, 32(3): 199-209.
48 Gong Y, Liu W, Huang X, et al. Antifungal activity and potential mechanism of N-butylphthalide alone and in combination with fluconazole against Candida albicans [J]. Front Microbiol, 2019, 10: 1461.
49 Li X, Yu C, Huang X, et al. Synergistic effects and mechanisms of budesonide in combination with fluconazole against resistant Candida albicans [J]. PLoS One, 2016, 11(12): e0168936.
50 Zhao R, Davey M, Hsu YC, et al. Navigating the chaperone network: an integrative map of physical and genetic interactions mediated by the hsp90 chaperone[J]. Cell, 2005, 120(5): 715-727.
51 Cruz MC, Goldstein AL, Blankenship JR, et al. Calcineurin is essential for survival during membrane stress in Candida albicans [J]. EMBO J, 2002, 21(4): 546-559.
52 Siegal ML, Promislow DE, Bergman A. Functional and evolutionary inference in gene networks: does topology matter[J]. Genetica, 2007, 129(1): 83-103.
53 Ebrahimi-Shaghaghi F, Noormohammadi Z, Atyabi SM, et al. Inhibitory effects of cold atmospheric plasma on the growth, virulence factors and HSP90 gene expression in Candida albicans [J]. Arch Biochem Biophys, 2021, 700: 108772.
54 O’Meara TR, Robbins N, Cowen LE. The Hsp90 chaperone network modulates candida virulence traits[J]. Trends Microbiol, 2017, 25(10): 809-819.
55 Zierer BK, Rubbelke M, Tippel F, et al. Importance of cycle timing for the function of the molecular chaperone Hsp90[J]. Nat Struct Mol Biol, 2016, 23(11): 1020-1028.
56 Whitesell L, Robbins N, Huang DS, et al. Structural basis for species-selective targeting of Hsp90 in a pathogenic fungus[J]. Nat Commun, 2019, 10(1): 402.
57 Garnaud C, Garcia-Oliver E, Wang Y, et al. The rim pathway mediates antifungal tolerance in Candida albicans through newly identified rim101 transcriptional targets, including Hsp90 and Ipt1[J]. Antimicrob Agents Chemother, 2018, 62(3): e01785-17.
58 Becker JW, Rotonda J, McKeever BM, et al. FK-506-binding protein: three-dimensional structure of the complex with the antagonist L-685818[J]. J Biol Chem, 1993, 268(15): 11335-11339.
59 Juvvadi PR, Fox D 3rd, Bobay BG, et al. Harnessing calcineurin-FK506-FKBP12 crystal structures from invasive fungal pathogens to develop antifungal agents[J]. Nat Commun, 2019, 10(1): 4275.
60 Li L, Zhang T, Xu J, et al. The synergism of the small molecule ENOblock and fluconazole against fluconazole-resistant Candida albicans [J]. Front Microbiol, 2019, 10: 2071.
61 Lu MJ, Yu CX, Cui XY, et al. Gentamicin synergises with azoles against drug-resistant Candida albicans [J]. Int J Antimicrob Agents, 2018, 51(1): 107-114.
62 Zhang M, Yan H, Lu M, et al. Corrigendum to “Antifungal activity of ribavirin used alone or in combination with fluconazole against Candida albicans is mediated by reduced virulence”[J]. Int J Antimicrob Agents, 2020, 55(3): 105917.
63 Zarnowski R, Sanchez H, Covelli AS, et al. Candida albicans biofilm-induced vesicles confer drug resistance through matrix biogenesis[J]. PLoS Biol 2018, 16(10): e2006872.
64 Deveau A, Hogan DA. Linking quorum sensing regulation and biofilm formation by Candida albicans [J]. Methods Mol Biol, 2011, 692: 219-233.
65 Singh BN, Upreti DK, Singh BR, et al. Quercetin sensitizes fluconazole-resistant Candida albicans to induce apoptotic cell death by modulating quorum sensing[J]. Antimicrob Agents Chemother, 2015, 59(4): 2153-2168.
66 Sharma M, Prasad R. The quorum-sensing molecule farnesol is a modulator of drug efflux mediated by ABC multidrug transporters and synergizes with drugs in Candida albicans [J]. Antimicrob Agents Chemother, 2011, 55(10): 4834-4843.
67 Yu LH, Wei X, Ma M, et al. Possible inhibitory molecular mechanism of farnesol on the development of fluconazole resistance in Candida albicans biofilm[J]. Antimicrob Agents Chemother, 2012, 56(2): 770-775.
68 Jia C, Zhang J, Zhuge Y, et al. Synergistic effects of geldanamycin with fluconazole are associated with reactive oxygen species in Candida tropicalis resistant to azoles and amphotericin B[J]. Free Radic Res, 2019, 53(6): 618-628.
69 Lee W, Woo ER, Lee DG. Effect of apigenin isolated from aster yomena against Candida albicans: apigenin-triggered apoptotic pathway regulated by mitochondrial calcium signaling[J]. J Ethnopharmacol, 2019, 231: 19-28.
70 Denning DW, Bromley MJ. How to bolster the antifungal pipeline[J]. Science, 2015, 347(6229): 1414-1416.
71 Ahmad A, Khan A, Manzoor N, et al. Evolution of ergosterol biosynthesis inhibitors as fungicidal aga-inst Candida[J]. Microb Pathog, 2010, 48(1): 35-41.
72 Ahmad A, Khan A, Khan LA, et al. In vitro synergy of eugenol and methyleugenol with fluconazole against clinical Candida isolates [J]. J Med Microbiol, 2010, 59(10): 1178-1184.
73 Pfaller MA. Antifungal drug resistance: mechanisms, epidemiology, and consequences for treatment[J]. Am J Med, 2012, 125(1 ): S3-S13.
74 Ahmad A, Wani MY, Khan A, et al. Synergistic interactions of eugenol-tosylate and its congeners with fluconazole against Candida albicans [J]. PLoS One, 2015, 10(12): e0145053.
75 Nishimoto AT, Wiederhold NP, Flowers SA, et al. In vitro activities of the novel investigational tetrazoles VT-1161 and VT-1598 compared to the triazole antifungals against azole-resistant strains and clinical iolates of Candida albicans [J]. Antimicrob Agents Chemother, 2019, 63(6): e00341-19.
76 Prasad R, Shah AH, Rawal MK. Antifungals: mechanism of action and drug resistance[J]. Adv Exp Med Biol, 2016, 892: 327-349.
77 Silva S, Henriques M, Hayes A, et al. Candida glabrata and Candida albicans co-infection of an in vitro oral epithelium[J]. J Oral Pathol Med, 2011, 40(5): 421-427.
78 Pathak AK, Sharma S, Shrivastva P. Multi-species biofilm of Candida albicans and non-Candida albicans Candida species on acrylic substrate[J]. J Appl Oral Sci, 2012, 20(1): 70-75.
79 Cieslik W, Szczepaniak J, Krasowska A, et al. Antifungal styryloquinolines as Candida albicans efflux pump inhibitors: styryloquinolines are ABC transporter inhibitors[J]. Molecules, 2020, 25(2): 345.
80 Day AM, Quinn J. Stress-activated protein kinases in human fungal pathogens[J]. Front Cell Infect Microbiol, 2019, 9: 261.
81 Navarro-Garcia F, Sanchez M, Pla J, et al. Functional characterization of the MKC1 gene of Candida albicans, which encodes a mitogen-activated protein kinase homolog related to cell integrity[J]. Mol Cell Biol, 1995, 15(4): 2197-2206.
82 Correia I, Wilson D, Hube B, et al. Characterization of a Candida albicans mutant defective in all MA-PKs highlights the major role of Hog1 in the MAPK signaling network[J]. J Fungi (Basel), 2020, 6(4): 230.
83 Gopal D, Muddebihalkar AG, Skariyachan S, et al. Mitogen activated protein kinase-1 and cell division control protein-42 are putative targets for the binding of novel natural lead molecules: a therapeutic intervention against Candida albicans [J]. J Biomol Struct Dyn, 2020, 38(15): 4584-4599.
84 Correia I, Prieto D, Roman E, et al. Cooperative role of MAPK pathways in the interaction of Candida albicans with the host epithelium[J]. Microorganisms, 2019, 8(1): 48.
85 Roman E, Correia I, Prieto D, et al. The HOG MAPK pathway in Candida albicans: more than an osmosensing pathway[J]. Int Microbiol, 2020, 23(1): 23-29.
86 Dai BD, Wang Y, Li DD, et al. Hsp90 is involved in apoptosis of Candida albicans by regulating the calcineurin-caspase apoptotic pathway[J]. PLoS One, 2012, 7(9): e45109.
87 Jordao CC, Klein MI, Carmello JC, et al. Consecutive treatments with photodynamic therapy and nystatin altered the expression of virulence and ergosterol biosynthesis genes of a fluconazole-resistant Candida albicans in vivo [J]. Photodiagn Photodyn, 2021, 33: a102155.
[1] 李姗姗,杨芳. 变异链球菌与白色念珠菌相互作用在龋病发生中的研究进展[J]. 国际口腔医学杂志, 2022, 49(4): 392-396.
[2] 刘千溪,吴佳益,任彪,黄睿洁. 粪肠球菌与口腔微生物相互作用的研究进展[J]. 国际口腔医学杂志, 2022, 49(3): 290-295.
[3] 黄培勍,彭显,徐欣. 口腔挥发性硫化物的产生与针对性防治的研究进展[J]. 国际口腔医学杂志, 2021, 48(5): 592-599.
[4] 李诗佳,陈秋宇,邹静,黄睿洁. 尼古丁对口腔细菌单独或混合培养时菌群数目调控的研究[J]. 国际口腔医学杂志, 2021, 48(3): 305-311.
[5] 熊开新,邹玲. 白色念珠菌、黏性放线菌与根面龋相关性的研究进展[J]. 国际口腔医学杂志, 2021, 48(2): 187-191.
[6] 李帆,张利娟,谭凯璇,张颖,卢洁,李姗姗,杨芳. 基于重水拉曼技术的氯己定对白色念珠菌抑菌效能的研究[J]. 国际口腔医学杂志, 2021, 48(1): 35-40.
[7] 文书琼,郭君怡,戴文晓,王迪侃,王智. 白色念珠菌影响口腔黏膜癌变的机制进展[J]. 国际口腔医学杂志, 2019, 46(6): 705-710.
[8] 杜倩,任彪,周学东,徐欣. 根面龋微生态的研究进展[J]. 国际口腔医学杂志, 2019, 46(3): 326-332.
[9] 郝一龙,周瑜,陈谦明. 正中菱形舌炎发病危险因素的研究进展[J]. 国际口腔医学杂志, 2019, 46(3): 333-338.
[10] 杨子,侯本祥. 持续性根尖周炎根管内外生物膜特性的研究进展[J]. 国际口腔医学杂志, 2019, 46(2): 238-243.
[11] 房宏志, 田媛媛, 喻譞, 杨英明, 杨惠, 胡涛. 不同蔗糖浓度下外源性右旋糖酐酶与氟化钠对粘放线菌生物膜的影响[J]. 国际口腔医学杂志, 2017, 44(6): 654-659.
[12] 刘诗雨, 田宓, 石黎冉, 潘韦霖, 王一尧, 李明云. 尼古丁和美卡拉明对牙周致病微生物的影响[J]. 国际口腔医学杂志, 2017, 44(4): 421-425.
[13] 陆笑, 翁春辉, 王劲茗, 刘少娟, 刘芹, 林珊. luxSem>/AI-2密度感应对缓症链球菌生物膜致病力的影响[J]. 国际口腔医学杂志, 2017, 44(4): 411-420.
[14] 周双双 郑欣 周学东 徐欣. 菌斑生物膜产碱代谢与龋病[J]. 国际口腔医学杂志, 2016, 43(5): 573-577.
[15] 朱宸佑,邓佳,曹钰彬,刘孟轲,杨醒眉. 生物膜在位点保护中的应用[J]. 国际口腔医学杂志, 2016, 43(2): 187-189.
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed   
[1] 张新春. 桩冠修复与无髓牙的保护[J]. 国际口腔医学杂志, 1999, 26(06): .
[2] 王昆润. 长期单侧鼻呼吸对头颅发育有不利影响[J]. 国际口腔医学杂志, 1999, 26(05): .
[3] 彭国光. 颈淋巴清扫术中颈交感神经干的解剖变异[J]. 国际口腔医学杂志, 1999, 26(05): .
[4] 杨凯. 淋巴化疗的药物运载系统及其应用现状[J]. 国际口腔医学杂志, 1999, 26(05): .
[5] 康非吾. 种植义齿下部结构生物力学研究进展[J]. 国际口腔医学杂志, 1999, 26(05): .
[6] 柴枫. 可摘局部义齿用Co-Cr合金的激光焊接[J]. 国际口腔医学杂志, 1999, 26(04): .
[7] 孟姝,吴亚菲,杨禾. 伴放线放线杆菌产生的细胞致死膨胀毒素及其与牙周病的关系[J]. 国际口腔医学杂志, 2005, 32(06): 458 -460 .
[8] 费晓露,丁一,徐屹. 牙周可疑致病菌对口腔黏膜上皮的粘附和侵入[J]. 国际口腔医学杂志, 2005, 32(06): 452 -454 .
[9] 赵兴福,黄晓晶. 变形链球菌蛋白组学研究进展[J]. 国际口腔医学杂志, 2008, 35(S1): .
[10] 庞莉苹,姚江武. 抛光和上釉对陶瓷表面粗糙度、挠曲强度及磨损性能的影响[J]. 国际口腔医学杂志, 2008, 35(S1): .