白色念珠菌抗藥性的產生造成臨床治療上很大的困難，因此急需開發新的抗真菌藥物。在本研究中，我們探討P-113所衍生出來的兩個新抗菌胜肽P-113Du和P-113Tri。此二個抗菌胜肽具有比P-113還要多的正電荷、更高的α-螺旋的程度及等電點。此外，P-113Du和P-113Tri對於白色念珠菌、革蘭氏陰性細菌及革蘭氏陽性細菌都有更好的殺菌能力。同時三種抗菌胜肽對於人類牙齦表皮S-G細胞都具有很低的細胞毒性。此外，我們也使用細胞敏感性和競爭實驗，深入探討P-113Du和P-113Tri對於白色念珠菌的殺菌機制。結果發現細胞壁的醣類會與抗菌胜肽產生交互作用，尤其是細胞壁上的甘露聚糖和葡聚糖會影響抗菌胜肽的殺菌能力。另外，我們使用一系列細胞壁受損的突變菌株，進一步了解醣類與抗菌胜肽之間的交互作用。實驗結果指出磷酸甘露聚糖和N鍵結甘露聚糖缺失的突變菌株會降低抗菌胜肽附著到白色念珠菌的比例。此外，外加帶有磷酸的醣會降低抗菌胜肽的殺菌能力，證實帶負電的磷酸會幫助抗菌胜肽與醣類鍵結。P-113Du和P-113Tri不僅會貼附於細胞表面，同樣也能攻擊細胞質中的胞器，例如液泡。然而，絕大部分的P-113都會快速的進入細胞質而不存在於細胞表面。並且P-113Tri不需要使用能量就可以穿破細胞膜，而P-113Du和P-113的殺菌作用則會受到能量缺乏的影響。這些結果指出P-113、P-113Du和P-113Tri與細胞壁上的醣類、N鍵結甘露聚糖和磷酸甘露聚糖有不同的鍵結能力，並可透過不同的方式進入細胞而造成細胞死亡。最後，我們發現P-113會攻擊粒線體，而且P-113Du和P-113Tri可以促使產生大量自由基。總和而論，我們的研究顯示P-113Du和P-113Tri 可以作為一個發展具有多重目標但低細胞毒性的新型抗真菌藥物。

The emergence of antifungal drug resistance in C. albicans is problematic in the clinical setting. To develop new antifungal drugs is therefore in high demand. In this study, two novel derivatives of the antimicrobial peptide (AMP) P-113, P-113Du and P-113Tri, were characterized. Notably, P-113Du and P-113Tri contain more positive charge, higher α-helical contents and pI, compared to their parental P-113. Moreover, P-113Du and P-113Tri exhibited a strong antimicrobial activity against C. albicans and various Gram-negative and Gram-positive bacteria. Importantly, all the three peptides exhibited a low level of cytotoxicity to the human gingival epithelioid S-G cells. To further investigate the mechanisms of P-113Du and P-113Tri against C. albicans, cell susceptibility and competition assays were performed. The results showed the interaction between cell-wall polysaccharides and the peptides. Particularly, mannan and glucan on the cell wall play an important role to mediate candidacidal activity of the peptides. To reveal details of the polysaccharides-peptide interaction, a range of cell wall-defective mutants of C. albicans were also used. The results indicated that the loss of phosphomannan and N-linked mannan in the cell-wall defective mutants is correlated with the reduced peptide binding to C. albicans cells. Moreover, exogenous polysaccharides carrying phosphate moieties reduced the efficacy of the AMPs, suggesting the negative charged phosphosugar also attributes to the peptide binding to polysaccharides. Interestingly, P-113Du and P-113Tri not only bind to the cell surface, but also gain entry into the cytosol targeting to organelles such as vacuoles. However, most of P-113 was rapidly translocated into the cytosol without localizing on the cell surface. Moreover, P-113Tri penetrated cell membrane independent of energy, whereas the candidacidal activity of P-113 and P-113Du was affected by energy depletion. These results suggest that P-113, P-113Du and P-113Tri have different preference to interact with cell wall glycans, N-link mannan and phosphomannan, and utilize different ways to get into the cells and cause cell death. Finally, we also found that P-113 can target to mitochondria, and P-113Du and P-113Tri largely induce ROS production. Together, our findings suggest that P-113Du and P-113Tri are promising candidates for development of new antifungal agents with multi-targets and a low cytotoxicity.

中文摘要 I
Abstract II
致謝辭 III
Table of Contents V
List of Tables VIII
List of Figures IX
Supplementary materials X
List of papers and patents published during Ph.D. study XI
Abbreviation XII
Chapter 1 Introduction 1
1.1 Candida albicans 2
1.2 Filamentation and virulence/pathogenesis of C. albicans 2
1.2.1. Regulation of C. albicans yeast-filament transition 2
1.2.2. Relationship between filamentation and C. albicans virulence/pathogenesis 3
1.3 Candida cell wall 3
1.3.1. Cell wall components of C. albicans 3
1.3.2. N-glycosylation pathway of C. albicans 4
1.3.3. O-glycosylation pathway of C. albicans 5
1.3.4. Immune recognition of C. albicans cell wall polysaccharides 5
1.4 Antimicrobial resistance (AMR) 6
1.4.1. Epidemiology of Candida species and clinically used antifungal drugs 6
1.4.2. AMR of C. glabrata 7
1.4.3. AMR of C. parapsilosis and other Candida species 7
1.4.4. AMR of C. auris 8
1.5 Antimicrobial peptides (AMPs) 8
1.6 Structure of AMPs 9
1.6.1. α-helical AMPs 9
1.6.2. β-sheet AMPs 10
1.6.3. Extended AMPs 11
1.7 Antimicrobial mechanisms of AMPs 11
1.7.1. The membrane permeabilization mechanism 11
1.7.2. Cell wall and intracellular targeting mechanisms of AMPs 13
1.8 Histatin peptides: functions and mechanisms 14
1.8.1. Multiple functions of histatin peptides 14
1.8.2. Antifungal and antibacterial activity of histatin-5 14
1.8.3. Antifungal mechanism of histatin-5 15
1.9 P-113: a derivative peptide from histatin-5 18
1.10 Specific aims of this study 19
Chapter 2 Materials and Methods 20
2.1 Antifungal peptides and reagents 21
2.2 C. albicans strains, media, and growth conditions 21
2.3 Time- and dose-dependent killing assay for C. albicans 21
2.4 Determination of antibiotic and P-113 susceptibility of clinical isolates of Candida spp. 21
2.5 Circular dichroism spectroscopy 22
2.6 C. albicans killing assay 22
2.7 Bactericidal assay 23
2.8 Determination of the minimum inhibitory concentration (MIC) for bacteria 23
2.9 Cytotoxicity assay 24
2.10 Confocal scanning laser microscopy 24
2.11 Binding of P-113, P-113Du and P-113Tri to C. albicans cells 24
2.12 β-Glucan staining 25
2.13 Competition assays 25
2.14 Measurement of minimum inhibitory concentrations (MICs) for C. albicans 26
2.15 Measurement of dissociation constants for peptide/glycan complexes 26
2.16 Glycan microarray analysis 26
2.17 Kinetics of membrane permeabilization 27
2.18 Reactive oxygen species (ROS) production 27
2.19 Statistical analysis 27
Chapter 3 Results 28
3.1 Rapid killing of C. albicans by P-113 29
3.2 P-113 killing of drug-resistant Candida clinical isolates 29
3.3 Structural and physicochemical properties of novel peptides P-113Du and P-113Tri 29
3.4 Candidacidal activity of P-113, P-113Du and P-113Tri 31
3.5 Broad-spectrum antibacterial activity of P-113Du and P-113Tri 31
3.6 Cytotoxicity of P-113, P-113Du and P-113Tri 32
3.7 P-113Du and P-113Tri interact with cell surface of C. albicans 32
3.8 P-113Du and P-113Tri bind to C. albicans cell-wall carbohydrates 32
3.9 Binding to N-linked mannan structure has a profound role in antifungal activity of the peptides 34
3.10 Peptide binding with phosphomannan also plays a role in antifungal activity of the peptides 36
3.11 Identification of the potential targeted glycans by a glycan array screening 37
3.12 Membrane disruption by P-113Du and P-113Tri 38
3.13 Candidacidal activities of P-113Tri is energy-independent 39
3.14 Mitochondrial complex I subunits may be a potential intracellular target for P-113 39
3.15 ROS production induced by P-113Du and P-113Tri 40
Chapter 4 Discussion and Future Perspectives 41
References 51
Tables 83
Figures 92
Supplementary Materials 117

1. Moran, G., Coleman, D., and Sullivan, D. (2012) An introduction to the medically important Candida species. in Candida and Candidiasis, Second Edition, American Society of Microbiology. pp 11-25.
2. Odds, F. C. (1988) Candida and candidosis: a review and bibliography, Bailliere Tindall.
3. Odds, F. C. (1994) Pathogenesis of Candida infections. Journal of the American Academy of Dermatology 31, S2-5.
4. Dupont, P. F. (1995) Candida albicans, the opportunist. A cellular and molecular perspective. Journal of the American Podiatric Medical Association 85, 104-115.
5. Pfaller, M. A., Andes, D. R., Diekema, D. J., Horn, D. L., Reboli, A. C., Rotstein, C., Franks, B., and Azie, N. E. (2014) Epidemiology and outcomes of invasive candidiasis due to non-albicans species of Candida in 2,496 patients: data from the Prospective Antifungal Therapy (PATH) registry 2004-2008. PLOS One 9, e101510.
6. Azie, N., Neofytos, D., Pfaller, M., Meier-Kriesche, H. U., Quan, S. P., and Horn, D. (2012) The PATH (Prospective Antifungal Therapy) Alliance® registry and invasive fungal infections: update 2012. Diagnostic Microbiology and Infectious Disease 73, 293-300.
7. Shepherd, M. G., Poulter, R. T., and Sullivan, P. A. (1985) Candida albicans: biology, genetics, and pathogenicity. Annual Review of Microbiology 39, 579-614.
8. Edmond, M. B., Wallace, S. E., McClish, D. K., Pfaller, M. A., Jones, R. N., and Wenzel, R. P. (1999) Nosocomial bloodstream infections in United States hospitals: a three-year analysis. Clinical Infectious Diseases 29, 239-244.
9. Wisplinghoff, H., Bischoff, T., Tallent, S. M., Seifert, H., Wenzel, R. P., and Edmond, M. B. (2004) Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clinical Infectious Diseases 39, 309-317.
10. Castanheira, M., Messer, S. A., Rhomberg, P. R., and Pfaller, M. A. (2016) Antifungal susceptibility patterns of a global collection of fungal isolates: results of the SENTRY Antifungal Surveillance Program (2013). Diagnostic Microbiology and Infectious Disease 85, 200-204.
11. Mitchell, A. P. (1998) Dimorphism and virulence in Candida albicans. Current Opinion in Microbiology 1, 687-692.
12. Brandt, M. E. (2002) Candida and Candidiasis. Emerging Infectious Diseases 8, 876-876.
13. Biswas, S., Van Dijck, P., and Datta, A. (2007) Environmental sensing and signal transduction pathways regulating morphopathogenic determinants of Candida albicans. Microbiology and Molecular Biology Reviews 71, 348-376.
14. Kumamoto, C. A., and Vinces, M. D. (2005) Contributions of hyphae and hypha-co-regulated genes to Candida albicans virulence. Cellular Microbiology 7, 1546-1554.
15. Ernst, J. F. (2000) Transcription factors in Candida albicans - environmental control of morphogenesis. Microbiology 146 (Pt 8), 1763-1774.
16. Shapiro, R. S., Robbins, N., and Cowen, L. E. (2011) Regulatory circuitry governing fungal development, drug resistance, and disease. Microbiology and Molecular Biology Reviews 75, 213-267.
17. Silva, A. C., Xu, X., Kim, H. S., Fillingham, J., Kislinger, T., Mennella, T. A., and Keogh, M. C. (2012) The replication-independent histone H3-H4 chaperones HIR, ASF1, and RTT106 co-operate to maintain promoter fidelity. The Journal of Biological Chemistry 287, 1709-1718.
18. Amin, A. D., Vishnoi, N., and Prochasson, P. (2013) A global requirement for the HIR complex in the assembly of chromatin. Biochimica et Biophysica Acta 1819, 264-276.
19. Green, E. M., Antczak, A. J., Bailey, A. O., Franco, A. A., Wu, K. J., Yates, J. R., 3rd, and Kaufman, P. D. (2005) Replication-independent histone deposition by the HIR complex and Asf1. Current Biology 15, 2044-2049.
20. Kim, J., Lee, J. E., and Lee, J. S. (2015) Histone deacetylase-mediated morphological transition in Candida albicans. Journal of Microbiology 53, 805-811.
21. O'Meara, T. R., Veri, A. O., Ketela, T., Jiang, B., Roemer, T., and Cowen, L. E. (2015) Global analysis of fungal morphology exposes mechanisms of host cell escape. Nature Communications 6, 6741.
22. Ramage, G., Saville, S. P., Thomas, D. P., and Lopez-Ribot, J. L. (2005) Candida biofilms: an update. Eukaryotic Cell 4, 633-638.
23. Sherwood, J., Gow, N. A., Gooday, G. W., Gregory, D. W., and Marshall, D. (1992) Contact sensing in Candida albicans: a possible aid to epithelial penetration. Journal of Medical and Veterinary Mycology 30, 461-469.
24. Lo, H. J., Kohler, J. R., DiDomenico, B., Loebenberg, D., Cacciapuoti, A., and Fink, G. R. (1997) Nonfilamentous C. albicans mutants are avirulent. Cell 90, 939-949.
25. Zheng, X., Wang, Y., and Wang, Y. (2004) Hgc1, a novel hypha-specific G1 cyclin-related protein regulates Candida albicans hyphal morphogenesis. The EMBO Journal 23, 1845-1856.
26. Carlisle, P. L., Banerjee, M., Lazzell, A., Monteagudo, C., Lopez-Ribot, J. L., and Kadosh, D. (2009) Expression levels of a filament-specific transcriptional regulator are sufficient to determine Candida albicans morphology and virulence. Proceedings of the National Academy of Sciences of the United States of America 106, 599-604.
27. Cleary, I. A., Reinhard, S. M., Lazzell, A. L., Monteagudo, C., Thomas, D. P., Lopez-Ribot, J. L., and Saville, S. P. (2016) Examination of the pathogenic potential of Candida albicans filamentous cells in an animal model of haematogenously disseminated candidiasis. FEMS Yeast Research 16, fow011.
28. Monniot, C., Boisrame, A., Da Costa, G., Chauvel, M., Sautour, M., Bougnoux, M. E., Bellon-Fontaine, M. N., Dalle, F., d'Enfert, C., and Richard, M. L. (2013) Rbt1 protein domains analysis in Candida albicans brings insights into hyphal surface modifications and Rbt1 potential role during adhesion and biofilm formation. PLOS One 8, e82395.
29. Rohm, M., Lindemann, E., Hiller, E., Ermert, D., Lemuth, K., Trkulja, D., Sogukpinar, O., Brunner, H., Rupp, S., Urban, C. F., and Sohn, K. (2013) A family of secreted pathogenesis-related proteins in Candida albicans. Molecular Microbiology 87, 132-151.
30. Braun, B. R., Head, W. S., Wang, M. X., and Johnson, A. D. (2000) Identification and characterization of TUP1-regulated genes in Candida albicans. Genetics 156, 31-44.
31. Richardson, J. P., Mogavero, S., Moyes, D. L., Blagojevic, M., Kruger, T., Verma, A. H., Coleman, B. M., De La Cruz Diaz, J., Schulz, D., Ponde, N. O., Carrano, G., Kniemeyer, O., Wilson, D., Bader, O., Enoiu, S. I., Ho, J., Kichik, N., Gaffen, S. L., Hube, B., and Naglik, J. R. (2018) Processing of Candida albicans Ece1p is critical for candidalysin maturation and fungal virulence. mBio 9, e02178-17.
32. Pierce, C. G., Chaturvedi, A. K., Lazzell, A. L., Powell, A. T., Saville, S. P., McHardy, S. F., and Lopez-Ribot, J. L. (2015) A novel small molecule inhibitor of Candida albicans biofilm formation, filamentation and virulence with low potential for the development of resistance. NPJ Biofilms and Microbiomes 1, 15012.
33. Fazly, A., Jain, C., Dehner, A. C., Issi, L., Lilly, E. A., Ali, A., Cao, H., Fidel, P. L., Jr., Rao, R. P., and Kaufman, P. D. (2013) Chemical screening identifies filastatin, a small molecule inhibitor of Candida albicans adhesion, morphogenesis, and pathogenesis. Proceedings of the National Academy of Sciences of the United States of America 110, 13594-13599.
34. Romo, J. A., Pierce, C. G., Chaturvedi, A. K., Lazzell, A. L., McHardy, S. F., Saville, S. P., and Lopez-Ribot, J. L. (2017) Development of anti-virulence approaches for candidiasis via a novel series of small-molecule inhibitors of Candida albicans filamentation. mBio 8, e01991-17.
35. Vila, T., Romo, J. A., Pierce, C. G., McHardy, S. F., Saville, S. P., and Lopez-Ribot, J. L. (2017) Targeting Candida albicans filamentation for antifungal drug development. Virulence 8, 150-158.
36. Klis, F. M., de Koster, C. G., and Brul, S. (2014) Cell wall-related bionumbers and bioestimates of Saccharomyces cerevisiae and Candida albicans. Eukaryotic Cell 13, 2-9.
37. Yin, Q. Y., de Groot, P. W., de Jong, L., Klis, F. M., and De Koster, C. G. (2007) Mass spectrometric quantitation of covalently bound cell wall proteins in Saccharomyces cerevisiae. FEMS Yeast Research 7, 887-896.
38. Moreno-Ruiz, E., Ortu, G., de Groot, P. W., Cottier, F., Loussert, C., Prevost, M. C., de Koster, C., Klis, F. M., Goyard, S., and d'Enfert, C. (2009) The GPI-modified proteins Pga59 and Pga62 of Candida albicans are required for cell wall integrity. Microbiology 155, 2004-2020.
39. Chaffin, W. L. (2008) Candida albicans cell wall proteins. Microbiology and Molecular Biology Reviews 72, 495-544.
40. Klis, F. M., de Koster, C. G., and Brul, S. (2014) Cell wall-related bionumbers and bioestimates of Saccharomyces cerevisiae and Candida albicans. Eukaryotic Cell 13, 2-9.
41. Shibata, N., Arai, M., Haga, E., Kikuchi, T., Najima, M., Satoh, T., Kobayashi, H., and Suzuki, S. (1992) Structural identification of an epitope of antigenic factor 5 in mannans of Candida albicans NIH B-792 (serotype B) and J-1012 (serotype A) as beta-1,2-linked oligomannosyl residues. Infection and Immunity 60, 4100-4110.
42. Trinel, P. A., Lepage, G., Jouault, T., Strecker, G., and Poulain, D. (1997) Definitive chemical evidence for the constitutive ability of Candida albicans serotype A strains to synthesize beta-1,2 linked oligomannosides containing up to 14 mannose residues. FEBS Letters 416, 203-206.
43. Fradin, C., Slomianny, M. C., Mille, C., Masset, A., Robert, R., Sendid, B., Ernst, J. F., Michalski, J. C., and Poulain, D. (2008) Beta-1,2 oligomannose adhesin epitopes are widely distributed over the different families of Candida albicans cell wall mannoproteins and are associated through both N- and O-glycosylation processes. Infection and Immunity 76, 4509-4517.
44. Munro, C. A., Bates, S., Buurman, E. T., Hughes, H. B., Maccallum, D. M., Bertram, G., Atrih, A., Ferguson, M. A., Bain, J. M., Brand, A., Hamilton, S., Westwater, C., Thomson, L. M., Brown, A. J., Odds, F. C., and Gow, N. A. (2005) Mnt1p and Mnt2p of Candida albicans are partially redundant alpha-1,2-mannosyltransferases that participate in O-linked mannosylation and are required for adhesion and virulence. The Journal of Biological Chemistry 280, 1051-1060.
45. Klis, F. M., Sosinska, G. J., de Groot, P. W., and Brul, S. (2009) Covalently linked cell wall proteins of Candida albicans and their role in fitness and virulence. FEMS Yeast Research 9, 1013-1028.
46. Klis, F. M., Brul, S., and De Groot, P. W. (2010) Covalently linked wall proteins in ascomycetous fungi. Yeast 27, 489-493.
47. Ene, I. V., Adya, A. K., Wehmeier, S., Brand, A. C., MacCallum, D. M., Gow, N. A., and Brown, A. J. (2012) Host carbon sources modulate cell wall architecture, drug resistance and virulence in a fungal pathogen. Cellular Microbiology 14, 1319-1335.
48. Gow, N. A., and Hube, B. (2012) Importance of the Candida albicans cell wall during commensalism and infection. Current Opinion in Microbiology 15, 406-412.
49. Kornfeld, R., and Kornfeld, S. (1985) Assembly of asparagine-linked oligosaccharides. Annual Review of Biochemistry 54, 631-664.
50. Bates, S., Hughes, H. B., Munro, C. A., Thomas, W. P., MacCallum, D. M., Bertram, G., Atrih, A., Ferguson, M. A., Brown, A. J., Odds, F. C., and Gow, N. A. (2006) Outer chain N-glycans are required for cell wall integrity and virulence of Candida albicans. The Journal of Biological Chemistry 281, 90-98.
51. Southard, S. B., Specht, C. A., Mishra, C., Chen-Weiner, J., and Robbins, P. W. (1999) Molecular analysis of the Candida albicans homolog of Saccharomyces cerevisiae MNN9, required for glycosylation of cell wall mannoproteins. Journal of Bacteriology 181, 7439-7448.
52. Bai, C., Xu, X. L., Chan, F. Y., Lee, R. T., and Wang, Y. (2006) MNN5 encodes an iron-regulated alpha-1,2-mannosyltransferase important for protein glycosylation, cell wall integrity, morphogenesis, and virulence in Candida albicans. Eukaryotic Cell 5, 238-247.
53. Rayner, J. C., and Munro, S. (1998) Identification of the MNN2 and MNN5 mannosyltransferases required for forming and extending the mannose branches of the outer chain mannans of Saccharomyces cerevisiae. The Journal of Biological Chemistry 273, 26836-26843.
54. Mora-Montes, H. M., Bates, S., Netea, M. G., Castillo, L., Brand, A., Buurman, E. T., Diaz-Jimenez, D. F., Jan Kullberg, B., Brown, A. J., Odds, F. C., and Gow, N. A. (2010) A multifunctional mannosyltransferase family in Candida albicans determines cell wall mannan structure and host-fungus interactions. The Journal of Biological Chemistry 285, 12087-12095.
55. Hall, R. A., Bates, S., Lenardon, M. D., Maccallum, D. M., Wagener, J., Lowman, D. W., Kruppa, M. D., Williams, D. L., Odds, F. C., Brown, A. J., and Gow, N. A. (2013) The Mnn2 mannosyltransferase family modulates mannoprotein fibril length, immune recognition and virulence of Candida albicans. PLOS Pathogens 9, e1003276.
56. Bates, S., Hall, R. A., Cheetham, J., Netea, M. G., MacCallum, D. M., Brown, A. J., Odds, F. C., and Gow, N. A. (2013) Role of the Candida albicans MNN1 gene family in cell wall structure and virulence. BMC Research Notes 6, 294.
57. Mille, C., Bobrowicz, P., Trinel, P. A., Li, H., Maes, E., Guerardel, Y., Fradin, C., Martinez-Esparza, M., Davidson, R. C., Janbon, G., Poulain, D., and Wildt, S. (2008) Identification of a new family of genes involved in beta-1,2-mannosylation of glycans in Pichia pastoris and Candida albicans. The Journal of Biological Chemistry 283, 9724-9736.
58. Hobson, R. P., Munro, C. A., Bates, S., MacCallum, D. M., Cutler, J. E., Heinsbroek, S. E., Brown, G. D., Odds, F. C., and Gow, N. A. (2004) Loss of cell wall mannosylphosphate in Candida albicans does not influence macrophage recognition. The Journal of Biological Chemistry 279, 39628-39635.
59. Lengeler, K. B., Tielker, D., and Ernst, J. F. (2008) Protein-O-mannosyltransferases in virulence and development. Cellular and Molecular Life Sciences 65, 528-544.
60. Diaz-Jimenez, D. F., Mora-Montes, H. M., Hernandez-Cervantes, A., Luna-Arias, J. P., Gow, N. A., and Flores-Carreon, A. (2012) Biochemical characterization of recombinant Candida albicans mannosyltransferases Mnt1, Mnt2 and Mnt5 reveals new functions in O- and N-mannan biosynthesis. Biochemical and Biophysical Research Communications 419, 77-82.
61. Mora-Montes, H. M., Bates, S., Netea, M. G., Diaz-Jimenez, D. F., Lopez-Romero, E., Zinker, S., Ponce-Noyola, P., Kullberg, B. J., Brown, A. J., Odds, F. C., Flores-Carreon, A., and Gow, N. A. (2007) Endoplasmic reticulum alpha-glycosidases of Candida albicans are required for N glycosylation, cell wall integrity, and normal host-fungus interaction. Eukaryotic cell 6, 2184-2193.
62. Jang, J. H., Shin, H. W., Lee, J. M., Lee, H. W., Kim, E. C., and Park, S. H. (2015) An Overview of Pathogen Recognition Receptors for Innate Immunity in Dental Pulp. Mediators of Inflammation 2015, 794143.
63. Netea, M. G., Brown, G. D., Kullberg, B. J., and Gow, N. A. (2008) An integrated model of the recognition of Candida albicans by the innate immune system. Nature Reviews Microbiology 6, 67-78.
64. Plato, A., Hardison, S. E., and Brown, G. D. (2015) Pattern recognition receptors in antifungal immunity. Seminars in Immunopathology 37, 97-106.
65. Netea, M. G., Gow, N. A., Munro, C. A., Bates, S., Collins, C., Ferwerda, G., Hobson, R. P., Bertram, G., Hughes, H. B., Jansen, T., Jacobs, L., Buurman, E. T., Gijzen, K., Williams, D. L., Torensma, R., McKinnon, A., MacCallum, D. M., Odds, F. C., Van der Meer, J. W., Brown, A. J., and Kullberg, B. J. (2006) Immune sensing of Candida albicans requires cooperative recognition of mannans and glucans by lectin and Toll-like receptors. Journal of Clinical Investigation 116, 1642-1650.
66. Brown, G. D. (2011) Innate antifungal immunity: the key role of phagocytes. Annual Review of Immunology 29, 1-21.
67. Pfaller, M. A., and Diekema, D. J. (2007) Epidemiology of invasive candidiasis: a persistent public health problem. Clinical Microbiology Reviews 20, 133-163.
68. Pfaller, M. A., Diekema, D. J., Turnidge, J. D., Castanheira, M., and Jones, R. N. (2019) Twenty years of the SENTRY Antifungal Surveillance Program: results for Candida species from 1997-2016. Open Forum Infectious Diseases 6, S79-S94.
69. Zhou, Z. L., Lin, C. C., Chu, W. L., Yang, Y. L., and Lo, H. J. (2016) The distribution and drug susceptibilities of clinical Candida species in TSARY 2014. Diagnostic Microbiology and Infectious Disease 86, 399-404.
70. Perea, S., and Patterson, T. F. (2002) Antifungal resistance in pathogenic fungi. Clinical Infectious Diseases 35, 1073-1080.
71. Lamoth, F., Lockhart, S. R., Berkow, E. L., and Calandra, T. (2018) Changes in the epidemiological landscape of invasive candidiasis. Journal of Antimicrobial Chemotherapy 73, i4-i13.
72. Alexander, B. D., Johnson, M. D., Pfeiffer, C. D., Jimenez-Ortigosa, C., Catania, J., Booker, R., Castanheira, M., Messer, S. A., Perlin, D. S., and Pfaller, M. A. (2013) Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations. Clinical Infectious Diseases 56, 1724-1732.
73. Pham, C. D., Iqbal, N., Bolden, C. B., Kuykendall, R. J., Harrison, L. H., Farley, M. M., Schaffner, W., Beldavs, Z. G., Chiller, T. M., Park, B. J., Cleveland, A. A., and Lockhart, S. R. (2014) Role of FKS Mutations in Candida glabrata: MIC values, echinocandin resistance, and multidrug resistance. Antimicrobial Agents and Chemotherapy 58, 4690-4696.
74. Fraser, M., Borman, A. M., Thorn, R., and Lawrance, L. M. (2019) Resistance to echinocandin antifungal agents in the United Kingdom in clinical isolates of Candida glabrata: Fifteen years of interpretation and assessment. Medical Mycology, myz053.
75. Wang, H., Xu, Y. C., and Hsueh, P. R. (2016) Epidemiology of candidemia and antifungal susceptibility in invasive Candida species in the Asia-Pacific region. Future Microbiology 11, 1461-1477.
76. Cheng, M. F., Yang, Y. L., Yao, T. J., Lin, C. Y., Liu, J. S., Tang, R. B., Yu, K. W., Fan, Y. H., Hsieh, K. S., Ho, M., and Lo, H. J. (2005) Risk factors for fatal candidemia caused by Candida albicans and non-albicans Candida species. BMC Infectious Diseases 5, 22.
77. Vasilyeva, N. V., Raush, E. R., Rudneva, M. V., Bogomolova, T. S., Taraskina, A. E., Fang, Y., Zhang, F., and Klimko, N. N. (2018) Etiology of invasive candidosis agents in Russia: a multicenter epidemiological survey. Frontiers in Medicine 12, 84-91.
78. Govender, N. P., Patel, J., Magobo, R. E., Naicker, S., Wadula, J., Whitelaw, A., Coovadia, Y., Kularatne, R., Govind, C., Lockhart, S. R., and Zietsman, I. L. (2016) Emergence of azole-resistant Candida parapsilosis causing bloodstream infection: results from laboratory-based sentinel surveillance in South Africa. Journal of Antimicrobial Chemotherapy 71, 1994-2004.
79. Lin, C. C., Liu, C. P., Hsieh, F. C., Lee, C. M., and Wang, W. S. (2015) Antimicrobial susceptibility and clinical outcomes of Candida parapsilosis bloodstream infections in a tertiary teaching hospital in Northern Taiwan. Journal of Microbiology, Immunology and Infection 48, 552-558.
80. Asner, S. A., Giulieri, S., Diezi, M., Marchetti, O., and Sanglard, D. (2015) Acquired Multidrug Antifungal Resistance in Candida lusitaniae during Therapy. Antimicrobial Agents and Chemotherapy 59, 7715-7722.
81. Arendrup, M. C., and Patterson, T. F. (2017) Multidrug-resistant Candida: epidemiology, molecular mechanisms, and treatment. The Journal of Infectious Diseases 216, S445-s451.
82. Fekkar, A., Meyer, I., Brossas, J. Y., Dannaoui, E., Palous, M., Uzunov, M., Nguyen, S., Leblond, V., Mazier, D., and Datry, A. (2013) Rapid emergence of echinocandin resistance during Candida kefyr fungemia treatment with caspofungin. Antimicrobial Agents and Chemotherapy 57, 2380-2382.
83. Lockhart, S. R., Etienne, K. A., Vallabhaneni, S., Farooqi, J., Chowdhary, A., Govender, N. P., Colombo, A. L., Calvo, B., Cuomo, C. A., Desjardins, C. A., Berkow, E. L., Castanheira, M., Magobo, R. E., Jabeen, K., Asghar, R. J., Meis, J. F., Jackson, B., Chiller, T., and Litvintseva, A. P. (2017) Simultaneous emergence of multidrug-resistant Candida auris on 3 continents confirmed by whole-genome sequencing and epidemiological analyses. Clinical Infectious Diseases 64, 134-140.
84. Chowdhary, A., Sharma, C., and Meis, J. F. (2017) Candida auris: a rapidly emerging cause of hospital-acquired multidrug-resistant fungal infections globally. PLOS Pathogens 13, e1006290.
85. Satoh, K., Makimura, K., Hasumi, Y., Nishiyama, Y., Uchida, K., and Yamaguchi, H. (2009) Candida auris sp. nov., a novel ascomycetous yeast isolated from the external ear canal of an inpatient in a Japanese hospital. Microbiology and Immunology 53, 41-44.
86. Spivak, E. S., and Hanson, K. E. (2018) Candida auris: an Emerging Fungal Pathogen. Journal of Clinical Microbiology 56, e01588-17.
87. Colombo, A. L., Júnior, J. N., and Guinea, J. (2017) Emerging multidrug-resistant Candida species. Current Opinion in Infectious Diseases 30, 528-538.
88. Boman, H. G., and Hultmark, D. (1987) Cell-free immunity in insects. Annual Review of Microbiology 41, 103-126.
89. Fitton, J. E., Dell, A., and Shaw, W. V. (1980) The amino acid sequence of the delta haemolysin of Staphylococcus aureus. FEBS Letters 115, 209-212.
90. Park, S., Park, S. H., Ahn, H. C., Kim, S., Kim, S. S., Lee, B. J., and Lee, B. J. (2001) Structural study of novel antimicrobial peptides, nigrocins, isolated from Rana nigromaculata. FEBS Letters 507, 95-100.
91. Zasloff, M. (2002) Antimicrobial peptides of multicellular organisms. Nature 415, 389-395.
92. Tam, J. P., Wang, S., Wong, K. H., and Tan, W. L. (2015) Antimicrobial peptides from plants. Pharmaceuticals 8, 711-757.
93. Hoffmann, J. A., Kafatos, F. C., Janeway, C. A., and Ezekowitz, R. A. (1999) Phylogenetic perspectives in innate immunity. Science 284, 1313-1318.
94. Hancock, R. E., and Sahl, H. G. (2006) Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nature Biotechnology 24, 1551-1557.
95. Schittek, B., Hipfel, R., Sauer, B., Bauer, J., Kalbacher, H., Stevanovic, S., Schirle, M., Schroeder, K., Blin, N., Meier, F., Rassner, G., and Garbe, C. (2001) Dermcidin: a novel human antibiotic peptide secreted by sweat glands. Nature Immunology 2, 1133-1137.
96. Gordon, Y. J., Romanowski, E. G., and McDermott, A. M. (2005) A review of antimicrobial peptides and their therapeutic potential as anti-infective drugs. Current Eye Research 30, 505-515.
97. Nguyen, L. T., Haney, E. F., and Vogel, H. J. (2011) The expanding scope of antimicrobial peptide structures and their modes of action. Trends in Biotechnology 29, 464-472.
98. Huang, Y., Huang, J., and Chen, Y. (2010) Alpha-helical cationic antimicrobial peptides: relationships of structure and function. Protein & Cell 1, 143-152.
99. Seo, M. D., Won, H. S., Kim, J. H., Mishig-Ochir, T., and Lee, B. J. (2012) Antimicrobial peptides for therapeutic applications: a review. Molecules 17, 12276-12286.
100. Bondaryk, M., Staniszewska, M., Zielinska, P., and Urbanczyk-Lipkowska, Z. (2017) Natural antimicrobial peptides as inspiration for design of a new generation antifungal compounds. Journal of Fungi 3, E46.
101. Mahlapuu, M., Hakansson, J., Ringstad, L., and Bjorn, C. (2016) Antimicrobial peptides: an emerging category of therapeutic agents. Frontiers in Cellular and Infection Microbiology 6, 194.
102. Nicola, A. M., Albuquerque, P., Paes, H. C., Fernandes, L., Costa, F. F., Kioshima, E. S., Abadio, A. K. R., Bocca, A. L., and Felipe, M. S. (2019) Antifungal drugs: new insights in research & development. Pharmacology & Therapeutics 195, 21-38.
103. Swidergall, M., and Ernst, J. F. (2014) Interplay between Candida albicans and the antimicrobial peptide armory. Eukaryotic Cell 13, 950-957.
104. Blondelle, S. E., Lohner, K., and Aguilar, M. (1999) Lipid-induced conformation and lipid-binding properties of cytolytic and antimicrobial peptides: determination and biological specificity. Biochimica et Biophysica Acta 1462, 89-108.
105. Bulet, P., Stocklin, R., and Menin, L. (2004) Anti-microbial peptides: from invertebrates to vertebrates. Immunological Reviews 198, 169-184.
106. Mura, M., Wang, J., Zhou, Y., Pinna, M., Zvelindovsky, A. V., Dennison, S. R., and Phoenix, D. A. (2016) The effect of amidation on the behaviour of antimicrobial peptides. European Biophysics Journal 45, 195-207.
107. Zasloff, M. (1987) Magainins, a class of antimicrobial peptides from Xenopus skin: isolation, characterization of two active forms, and partial cDNA sequence of a precursor. Proceedings of the National Academy of Sciences of the United States of America 84, 5449-5453.
108. Zairi, A., Tangy, F., Bouassida, K., and Hani, K. (2009) Dermaseptins and magainins: antimicrobial peptides from frogs' skin-new sources for a promising spermicides microbicides-a mini review. Journal of Biomedicine and Biotechnology 2009, 452567.
109. Matsuzaki, K. (1999) Why and how are peptide-lipid interactions utilized for self-defense? Magainins and tachyplesins as archetypes. Biochimica et Biophysica Acta 1462, 1-10.
110. Matsuzaki, K. (1998) Magainins as paradigm for the mode of action of pore forming polypeptides. Biochimica et Biophysica Acta 1376, 391-400.
111. Chen, H. C., Brown, J. H., Morell, J. L., and Huang, C. M. (1988) Synthetic magainin analogues with improved antimicrobial activity. FEBS Letters 236, 462-466.
112. Hancock, R. E., Haney, E. F., and Gill, E. E. (2016) The immunology of host defence peptides: beyond antimicrobial activity. Nature Reviews Immunology 16, 321-334.
113. Sansom, M. S. (1991) The biophysics of peptide models of ion channels. Progress in Biophysics & Molecular Biology 55, 139-235.
114. Ketchem, R. R., Hu, W., and Cross, T. A. (1993) High-resolution conformation of gramicidin A in a lipid bilayer by solid-state NMR. Science 261, 1457-1460.
115. Takahashi, D., Shukla, S. K., Prakash, O., and Zhang, G. (2010) Structural determinants of host defense peptides for antimicrobial activity and target cell selectivity. Biochimie 92, 1236-1241.
116. Yeaman, M. R., and Yount, N. Y. (2003) Mechanisms of antimicrobial peptide action and resistance. Pharmacological Reviews 55, 27-55.
117. Lee, T. H., Hall, K. N., and Aguilar, M. I. (2016) Antimicrobial peptide structure and mechanism of action: a focus on the role of membrane structure. Current Topics in Medicinal Chemistry 16, 25-39.
118. Cornet, B., Bonmatin, J. M., Hetru, C., Hoffmann, J. A., Ptak, M., and Vovelle, F. (1995) Refined three-dimensional solution structure of insect defensin A. Structure 3, 435-448.
119. Dhople, V., Krukemeyer, A., and Ramamoorthy, A. (2006) The human beta-defensin-3, an antibacterial peptide with multiple biological functions. Biochimica et Biophysica Acta 1758, 1499-1512.
120. Garcia-Olmedo, F., Molina, A., Alamillo, J. M., and Rodriguez-Palenzuela, P. (1998) Plant defense peptides. Biopolymers 47, 479-491.
121. Matsuzaki, K., Yoneyama, S., Fujii, N., Miyajima, K., Yamada, K., Kirino, Y., and Anzai, K. (1997) Membrane permeabilization mechanisms of a cyclic antimicrobial peptide, tachyplesin I, and its linear analog. Biochemistry 36, 9799-9806.
122. Rao, A. G. (1999) Conformation and antimicrobial activity of linear derivatives of tachyplesin lacking disulfide bonds. Archives of Biochemistry and Biophysics 361, 127-134.
123. Kondejewski, L. H., Jelokhani-Niaraki, M., Farmer, S. W., Lix, B., Kay, C. M., Sykes, B. D., Hancock, R. E., and Hodges, R. S. (1999) Dissociation of antimicrobial and hemolytic activities in cyclic peptide diastereomers by systematic alterations in amphipathicity. The Journal of Biological Chemistry 274, 13181-13192.
124. Helmerhorst, E. J., Breeuwer, P., van't Hof, W., Walgreen-Weterings, E., Oomen, L. C., Veerman, E. C., Amerongen, A. V., and Abee, T. (1999) The cellular target of histatin 5 on Candida albicans is the energized mitochondrion. The Journal of Biological Chemistry 274, 7286-7291.
125. Brewer, D., Hunter, H., and Lajoie, G. (1998) NMR studies of the antimicrobial salivary peptides histatin 3 and histatin 5 in aqueous and nonaqueous solutions. Biochemistry and Cell Biology 76, 247-256.
126. Tsai, H., and Bobek, L. A. (1998) Human salivary histatins: promising anti-fungal therapeutic agents. Critical Reviews in Oral Biology & Medicine 9, 480-497.
127. Shi, J., Ross, C. R., Leto, T. L., and Blecha, F. (1996) PR-39, a proline-rich antibacterial peptide that inhibits phagocyte NADPH oxidase activity by binding to Src homology 3 domains of p47 phox. Proceedings of the National Academy of Sciences of the United States of America 93, 6014-6018.
128. Harwig, S. S., Kokryakov, V. N., Swiderek, K. M., Aleshina, G. M., Zhao, C., and Lehrer, R. I. (1995) Prophenin-1, an exceptionally proline-rich antimicrobial peptide from porcine leukocytes. FEBS letters 362, 65-69.
129. Lorenzini, D. M., da Silva, P. I., Jr., Fogaca, A. C., Bulet, P., and Daffre, S. (2003) Acanthoscurrin: a novel glycine-rich antimicrobial peptide constitutively expressed in the hemocytes of the spider Acanthoscurria gomesiana. Developmental & Comparative Immunology 27, 781-791.
130. Lawyer, C., Pai, S., Watabe, M., Borgia, P., Mashimo, T., Eagleton, L., and Watabe, K. (1996) Antimicrobial activity of a 13 amino acid tryptophan-rich peptide derived from a putative porcine precursor protein of a novel family of antibacterial peptides. FEBS letters 390, 95-98.
131. Selsted, M. E., Novotny, M. J., Morris, W. L., Tang, Y. Q., Smith, W., and Cullor, J. S. (1992) Indolicidin, a novel bactericidal tridecapeptide amide from neutrophils. The Journal of biological chemistry 267, 4292-4295.
132. Yau, W. M., Wimley, W. C., Gawrisch, K., and White, S. H. (1998) The preference of tryptophan for membrane interfaces. Biochemistry 37, 14713-14718.
133. Persson, S., Killian, J. A., and Lindblom, G. (1998) Molecular ordering of interfacially localized tryptophan analogs in ester- and ether-lipid bilayers studied by 2H-NMR. Biophysical Journal 75, 1365-1371.
134. Li, J., Koh, J. J., Liu, S., Lakshminarayanan, R., Verma, C. S., and Beuerman, R. W. (2017) Membrane active antimicrobial peptides: translating mechanistic insights to design. Frontiers in Neuroscience 11, 73.
135. Prasad, R., and Ghannoum, M. A. (1996) Lipids of pathogenic fungi, CRC press.
136. Tytler, E. M., Anantharamaiah, G. M., Walker, D. E., Mishra, V. K., Palgunachari, M. N., and Segrest, J. P. (1995) Molecular basis for prokaryotic specificity of magainin-induced lysis. Biochemistry 34, 4393-4401.
137. Mazu, T. K., Bricker, B. A., Flores-Rozas, H., and Ablordeppey, S. Y. (2016) The mechanistic targets of antifungal agents: an overview. Mini-Reviews in Medicinal Chemistry 16, 555-578.
138. Suchodolski, J., and Krasowska, A. (2019) Plasma membrane potential of Candida albicans measured by Di-4-ANEPPS fluorescence depends on growth phase and regulatory factors. Microorganisms 7, E110.
139. Hancock, R. E., and Chapple, D. S. (1999) Peptide antibiotics. Antimicrobial Agents and Chemotherapy 43, 1317-1323.
140. Epand, R. M., Walker, C., Epand, R. F., and Magarvey, N. A. (2016) Molecular mechanisms of membrane targeting antibiotics. Biochimica et Biophysica Acta 1858, 980-987.
141. Ehrenstein, G., and Lecar, H. (1977) Electrically gated ionic channels in lipid bilayers. Q. Annual Review of Biophysics 10, 1-34.
142. Kumar, P., Kizhakkedathu, J. N., and Straus, S. K. (2018) Antimicrobial peptides: diversity, mechanism of action and strategies to improve the activity and biocompatibility in vivo. Biomolecules 8, E4.
143. He, K., Ludtke, S. J., Heller, W. T., and Huang, H. W. (1996) Mechanism of alamethicin insertion into lipid bilayers. Biophysical Journal 71, 2669-2679.
144. Matsuzaki, K., Sugishita, K., Ishibe, N., Ueha, M., Nakata, S., Miyajima, K., and Epand, R. M. (1998) Relationship of membrane curvature to the formation of pores by magainin 2. Biochemistry 37, 11856-11863.
145. Matsuzaki, K., Yoneyama, S., and Miyajima, K. (1997) Pore formation and translocation of melittin. Biophysical Journal 73, 831-838.
146. Oren, Z., Lerman, J. C., Gudmundsson, G. H., Agerberth, B., and Shai, Y. (1999) Structure and organization of the human antimicrobial peptide LL-37 in phospholipid membranes: relevance to the molecular basis for its non-cell-selective activity. Biochemical Journal 341 (Pt 3), 501-513.
147. Rozek, A., Friedrich, C. L., and Hancock, R. E. (2000) Structure of the bovine antimicrobial peptide indolicidin bound to dodecylphosphocholine and sodium dodecyl sulfate micelles. Biochemistry 39, 15765-15774.
148. Munch, D., and Sahl, H. G. (2015) Structural variations of the cell wall precursor lipid II in Gram-positive bacteria - Impact on binding and efficacy of antimicrobial peptides. Biochimica et Biophysica Acta 1848, 3062-3071.
149. de Leeuw, E., Li, C., Zeng, P., Li, C., Diepeveen-de Buin, M., Lu, W. Y., Breukink, E., and Lu, W. (2010) Functional interaction of human neutrophil peptide-1 with the cell wall precursor lipid II. FEBS Letters 584, 1543-1548.
150. Tsai, P. W., Yang, C. Y., Chang, H. T., and Lan, C. Y. (2011) Characterizing the role of cell-wall beta-1,3-exoglucanase Xog1p in Candida albicans adhesion by the human antimicrobial peptide LL-37. PLOS One 6, e21394.
151. Li, X. S., Sun, J. N., Okamoto-Shibayama, K., and Edgerton, M. (2006) Candida albicans cell wall ssa proteins bind and facilitate import of salivary histatin 5 required for toxicity. The Journal of Biological Chemistry 281, 22453-22463.
152. Scocchi, M., Mardirossian, M., Runti, G., and Benincasa, M. (2016) Non-membrane permeabilizing modes of action of antimicrobial peptides on bacteria. Current Topics in Medicinal Chemistry 16, 76-88.
153. Park, C. B., Kim, H. S., and Kim, S. C. (1998) Mechanism of action of the antimicrobial peptide buforin II: buforin II kills microorganisms by penetrating the cell membrane and inhibiting cellular functions. Biochemical and Biophysical Research Communications 244, 253-257.
154. Boman, H. G., Agerberth, B., and Boman, A. (1993) Mechanisms of action on Escherichia coli of cecropin P1 and PR-39, two antibacterial peptides from pig intestine. Infection and Immunity 61, 2978-2984.
155. Oppenheim, F. G., Xu, T., McMillian, F. M., Levitz, S. M., Diamond, R. D., Offner, G. D., and Troxler, R. F. (1988) Histatins, a novel family of histidine-rich proteins in human parotid secretion. Isolation, characterization, primary structure, and fungistatic effects on Candida albicans. The Journal of Biological Chemistry 263, 7472-7477.
156. Johnson, D. A., Yeh, C. K., and Dodds, M. W. (2000) Effect of donor age on the concentrations of histatins in human parotid and submandibular/sublingual saliva. Arch. Oral Biol. 45, 731-740.
157. Troxler, R. F., Offner, G. D., Xu, T., Vanderspek, J. C., and Oppenheim, F. G. (1990) Structural relationship between human salivary histatins. Journal of Dental Research 69, 2-6.
158. Campese, M., Sun, X., Bosch, J. A., Oppenheim, F. G., and Helmerhorst, E. J. (2009) Concentration and fate of histatins and acidic proline-rich proteins in the oral environment. Archives of Oral Biology 54, 345-353.
159. Helmerhorst, E. J., Van't Hof, W., Veerman, E. C., Simoons-Smit, I., and Nieuw Amerongen, A. V. (1997) Synthetic histatin analogues with broad-spectrum antimicrobial activity. Biochemical Journal 326 (Pt 1), 39-45.
160. Messana, I., Cabras, T., Iavarone, F., Manconi, B., Huang, L., Martelli, C., Olianas, A., Sanna, M. T., Pisano, E., Sanna, M., Arba, M., D'Alessandro, A., Desiderio, C., Vitali, A., Pirolli, D., Tirone, C., Lio, A., Vento, G., Romagnoli, C., Cordaro, M., Manni, A., Gallenzi, P., Fiorita, A., Scarano, E., Calo, L., Passali, G. C., Picciotti, P. M., Paludetti, G., Fanos, V., Faa, G., and Castagnola, M. (2015) Chrono-proteomics of human saliva: variations of the salivary proteome during human development. Journal of Proteome Research 14, 1666-1677.
161. Messana, I., Cabras, T., Pisano, E., Sanna, M. T., Olianas, A., Manconi, B., Pellegrini, M., Paludetti, G., Scarano, E., Fiorita, A., Agostino, S., Contucci, A. M., Calo, L., Picciotti, P. M., Manni, A., Bennick, A., Vitali, A., Fanali, C., Inzitari, R., and Castagnola, M. (2008) Trafficking and postsecretory events responsible for the formation of secreted human salivary peptides: a proteomics approach. Molecular & Cellular Proteomics 7, 911-926.
162. Xu, L., Lal, K., and Pollock, J. J. (1992) Histatins 2 and 4 are autoproteolytic degradation products of human parotid saliva. Oral Microbiology and Immunology 7, 127-128.
163. Castagnola, M., Inzitari, R., Rossetti, D. V., Olmi, C., Cabras, T., Piras, V., Nicolussi, P., Sanna, M. T., Pellegrini, M., Giardina, B., and Messana, I. (2004) A cascade of 24 histatins (histatin 3 fragments) in human saliva. Suggestions for a pre-secretory sequential cleavage pathway. The Journal of Biological Chemistry 279, 41436-41443.
164. Wang, G. (2014) Human antimicrobial peptides and proteins. Pharmaceuticals 7, 545-594.
165. Tsai, H., and Bobek, L. A. (1997) Human salivary histatin-5 exerts potent fungicidal activity against Cryptococcus neoformans. Biochimica et Biophysica Acta 1336, 367-369.
166. Nikawa, H., Jin, C., Makihira, S., Hamada, T., and Samaranayake, L. P. (2002) Susceptibility of Candida albicans isolates from the oral cavities of HIV-positive patients to histatin-5. Journal of Prosthetic Dentistry 88, 263-267.
167. Cabras, T., Patamia, M., Melino, S., Inzitari, R., Messana, I., Castagnola, M., and Petruzzelli, R. (2007) Pro-oxidant activity of histatin 5 related Cu(II)-model peptide probed by mass spectrometry. Biochemical and Biophysical research communications 358, 277-284.
168. Ryley, H. C. (2001) Human antimicrobial peptides. Reviews in Medical Microbiology 12, 177-186.
169. Vitorino, R., Lobo, M. J., Duarte, J. R., Ferrer-Correia, A. J., Domingues, P. M., and Amado, F. M. (2005) The role of salivary peptides in dental caries. Biomedical Chromatography 19, 214-222.
170. Oudhoff, M. J., Blaauboer, M. E., Nazmi, K., Scheres, N., Bolscher, J. G., and Veerman, E. C. (2010) The role of salivary histatin and the human cathelicidin LL-37 in wound healing and innate immunity. Biological Chemistry 391, 541-548.
171. Oudhoff, M. J., Bolscher, J. G., Nazmi, K., Kalay, H., van 't Hof, W., Amerongen, A. V., and Veerman, E. C. (2008) Histatins are the major wound-closure stimulating factors in human saliva as identified in a cell culture assay. FASEB Journal 22, 3805-3812.
172. Jensen, J. L., Lamkin, M. S., and Oppenheim, F. G. (1992) Adsorption of human salivary proteins to hydroxyapatite: a comparison between whole saliva and glandular salivary secretions. Journal of Dental Research 71, 1569-1576.
173. Siqueira, W. L., Margolis, H. C., Helmerhorst, E. J., Mendes, F. M., and Oppenheim, F. G. (2010) Evidence of intact histatins in the in vivo acquired enamel pellicle. Journal of Dental Research 89, 626-630.
174. Xu, T., Levitz, S. M., Diamond, R. D., and Oppenheim, F. G. (1991) Anticandidal activity of major human salivary histatins. Infection and Immunity 59, 2549-2554.
175. Helmerhorst, E. J., Reijnders, I. M., van't Hof, W., Simoons-Smit, I., Veerman, E. C., and Amerongen, A. V. (1999) Amphotericin B- and fluconazole-resistant Candida spp., Aspergillus fumigatus, and other newly emerging pathogenic fungi are susceptible to basic antifungal peptides. Antimicrobial Agents and Chemotherapy 43, 702-704.
176. Pathirana, R. U., Friedman, J., Norris, H. L., Salvatori, O., McCall, A. D., Kay, J., and Edgerton, M. (2018) Fluconazole-resistant Candida auris is susceptible to salivary histatin 5 killing and to intrinsic host defenses. Antimicrobial Agents and Chemotherapy 62, e01872-17.
177. Curvelo, J. A. R., Moraes, D. C., Anjos, C. A. D., Portela, M. B., and Soares, R. M. A. (2019) Histatin 5 and human lactoferrin inhibit biofilm formation of a fluconazole resistant Candida albicans clinical isolate. Anais da Academia Brasileira de Ciências 91, e20180045.
178. Liao, H., Liu, S., Wang, H., Su, H., and Liu, Z. (2017) Efficacy of Histatin5 in a murine model of vulvovaginal candidiasis caused by Candida albicans. Pathogens and Disease 75, ftx072.
179. Moffa, E. B., Mussi, M. C., Xiao, Y., Garrido, S. S., Machado, M. A., Giampaolo, E. T., and Siqueira, W. L. (2015) Histatin 5 inhibits adhesion of C. albicans to reconstructed human oral epithelium. Frontiers in Microbiology 6, 885.
180. Welling, M. M., Brouwer, C. P., van 't Hof, W., Veerman, E. C., and Amerongen, A. V. (2007) Histatin-derived monomeric and dimeric synthetic peptides show strong bactericidal activity towards multidrug-resistant Staphylococcus aureus in vivo. Antimicrobial Agents and Chemotherapy 51, 3416-3419.
181. Fernandez-Presas, A. M., Marquez Torres, Y., Garcia Gonzalez, R., Reyes Torres, A., Becker Fauser, I., Rodriguez Barrera, H., Ruiz Garcia, B., Toloza Medina, R., Delgado Dominguez, J., and Molinari Soriano, J. L. (2018) Ultrastructural damage in Streptococcus mutans incubated with saliva and histatin 5. Archives of Oral Biology 87, 226-234.
182. Du, H., Puri, S., McCall, A., Norris, H. L., Russo, T., and Edgerton, M. (2017) Human salivary protein histatin 5 has potent bactericidal activity against ESKAPE pathogens. Frontiers in Cellular and Infection Microbiology 7, 41.
183. Gusman, H., Grogan, J., Kagan, H. M., Troxler, R. F., and Oppenheim, F. G. (2001) Salivary histatin 5 is a potent competitive inhibitor of the cysteine proteinase clostripain. FEBS Letters 489, 97-100.
184. Borgwardt, D. S., Martin, A. D., Van Hemert, J. R., Yang, J., Fischer, C. L., Recker, E. N., Nair, P. R., Vidva, R., Chandrashekaraiah, S., Progulske-Fox, A., Drake, D., Cavanaugh, J. E., Vali, S., Zhang, Y., and Brogden, K. A. (2014) Histatin 5 binds to Porphyromonas gingivalis hemagglutinin B (HagB) and alters HagB-induced chemokine responses. Scientific Reports 4, 3904.
185. Mochon, A. B., and Liu, H. (2008) The antimicrobial peptide histatin-5 causes a spatially restricted disruption on the Candida albicans surface, allowing rapid entry of the peptide into the cytoplasm. PLOS Pathogens 4, e1000190.
186. Baev, D., Li, X. S., Dong, J., Keng, P., and Edgerton, M. (2002) Human salivary histatin 5 causes disordered volume regulation and cell cycle arrest in Candida albicans. Infection and Immunity 70, 4777-4784.
187. Koshlukova, S. E., Lloyd, T. L., Araujo, M. W., and Edgerton, M. (1999) Salivary histatin 5 induces non-lytic release of ATP from Candida albicans leading to cell death. The Journal of Biological Chemistry 274, 18872-18879.
188. Baev, D., Rivetta, A., Vylkova, S., Sun, J. N., Zeng, G. F., Slayman, C. L., and Edgerton, M. (2004) The TRK1 potassium transporter is the critical effector for killing of Candida albicans by the cationic protein, Histatin 5. The Journal of Biological Chemistry 279, 55060-55072.
189. Raj, P. A., Soni, S. D., and Levine, M. J. (1994) Membrane-induced helical conformation of an active candidacidal fragment of salivary histatins. The Journal of Biological Chemistry 269, 9610-9619.
190. Raj, P. A., Marcus, E., and Sukumaran, D. K. (1998) Structure of human salivary histatin 5 in aqueous and nonaqueous solutions. Biopolymers 45, 51-67.
191. Raj, P. A., Edgerton, M., and Levine, M. J. (1990) Salivary histatin 5: dependence of sequence, chain length, and helical conformation for candidacidal activity. The Journal of Biological Chemistry 265, 3898-3905.
192. Jang, W. S., Bajwa, J. S., Sun, J. N., and Edgerton, M. (2010) Salivary histatin 5 internalization by translocation, but not endocytosis, is required for fungicidal activity in Candida albicans. Molecular Microbiology 77, 354-370.
193. Edgerton, M., Koshlukova, S. E., Lo, T. E., Chrzan, B. G., Straubinger, R. M., and Raj, P. A. (1998) Candidacidal activity of salivary histatins. Identification of a histatin 5-binding protein on Candida albicans. The Journal of Biological Chemistry 273, 20438-20447.
194. Li, X. S., Reddy, M. S., Baev, D., and Edgerton, M. (2003) Candida albicans Ssa1/2p is the cell envelope binding protein for human salivary histatin 5. The Journal of Biological Chemistry 278, 28553-28561.
195. Sun, J. N., Li, W., Jang, W. S., Nayyar, N., Sutton, M. D., and Edgerton, M. (2008) Uptake of the antifungal cationic peptide Histatin 5 by Candida albicans Ssa2p requires binding to non-conventional sites within the ATPase domain. Molecular Microbiology 70, 1246-1260.
196. Kumar, R., Chadha, S., Saraswat, D., Bajwa, J. S., Li, R. A., Conti, H. R., and Edgerton, M. (2011) Histatin 5 uptake by Candida albicans utilizes polyamine transporters Dur3 and Dur31 proteins. The Journal of Biological Chemistry 286, 43748-43758.
197. Tati, S., Li, R., Puri, S., Kumar, R., Davidow, P., and Edgerton, M. (2014) Histatin 5-spermidine conjugates have enhanced fungicidal activity and efficacy as a topical therapeutic for oral candidiasis. Antimicrobial Agents and Chemotherapy 58, 756-766.
198. Douglas, L. M., Martin, S. W., and Konopka, J. B. (2009) BAR domain proteins Rvs161 and Rvs167 contribute to Candida albicans endocytosis, morphogenesis, and virulence. Infection and Immunity 77, 4150-4160.
199. Jang, W. S., Bajwa, J. S., Sun, J. N., and Edgerton, M. (2010) Salivary histatin 5 internalization by translocation, but not endocytosis, is required for fungicidal activity in Candida albicans. Molecular Microbiology 77, 354-370.
200. Helmerhorst, E. J., Troxler, R. F., and Oppenheim, F. G. (2001) The human salivary peptide histatin 5 exerts its antifungal activity through the formation of reactive oxygen species. Proceedings of the National Academy of Sciences of the United States of America 98, 14637-14642.
201. Komatsu, T., Salih, E., Helmerhorst, E. J., Offner, G. D., and Oppenheim, F. G. (2011) Influence of histatin 5 on Candida albicans mitochondrial protein expression assessed by quantitative mass spectrometry. Journal of Proteome Research 10, 646-655.
202. Petruzzelli, R., Clementi, M. E., Marini, S., Coletta, M., Di Stasio, E., Giardina, B., and Misiti, F. (2003) Respiratory inhibition of isolated mammalian mitochondria by salivary antifungal peptide histatin-5. Biochemical and Biophysical Research Communications 311, 1034-1040.
203. da Rocha Curvelo, J. A., Reis de Sa, L. F., Moraes, D. C., Soares, R. M., and Ferreira-Pereira, A. (2018) Histatin-5 induces the reversal of Pdr5p mediated fluconazole resistance in Saccharomyces cerevisae. Journal de Mycologie Médicale 28, 137-142.
204. Gusman, H., Lendenmann, U., Grogan, J., Troxler, R. F., and Oppenheim, F. G. (2001) Is salivary histatin 5 a metallopeptide? Biochimica et Biophysica Acta 1545, 86-95.
205. Grogan, J., McKnight, C. J., Troxler, R. F., and Oppenheim, F. G. (2001) Zinc and copper bind to unique sites of histatin 5. FEBS Letters 491, 76-80.
206. Melino, S., Rufini, S., Sette, M., Morero, R., Grottesi, A., Paci, M., and Petruzzelli, R. (1999) Zn(2+) ions selectively induce antimicrobial salivary peptide histatin-5 to fuse negatively charged vesicles. Identification and characterization of a zinc-binding motif present in the functional domain. Biochemistry 38, 9626-9633.
207. Rydengard, V., Andersson Nordahl, E., and Schmidtchen, A. (2006) Zinc potentiates the antibacterial effects of histidine-rich peptides against Enterococcus faecalis. FEBS Journal 273, 2399-2406.
208. Houghton, E. A., and Nicholas, K. M. (2009) In vitro reactive oxygen species production by histatins and copper(I,II). Journal of Biological Inorganic Chemistry 14, 243-251.
209. Tay, W. M., Hanafy, A. I., Angerhofer, A., and Ming, L. J. (2009) A plausible role of salivary copper in antimicrobial activity of histatin-5--metal binding and oxidative activity of its copper complex. Bioorganic & Medicinal Chemistry Letters 19, 6709-6712.
210. Harford, C., and Sarkar, B. (1997) Amino terminal Cu (II)-and Ni (II)-binding (ATCUN) motif of proteins and peptides: metal binding, DNA cleavage, and other properties. Accounts of Chemical Research 30, 123-130.
211. Conklin, S. E., Bridgman, E. C., Su, Q., Riggs-Gelasco, P., Haas, K. L., and Franz, K. J. (2017) Specific histidine residues confer histatin peptides with copper-dependent activity against Candida albicans. Biochemistry 56, 4244-4255.
212. Cobine, P. A., Ojeda, L. D., Rigby, K. M., and Winge, D. R. (2004) Yeast contain a non-proteinaceous pool of copper in the mitochondrial matrix. The Journal of Biological Chemistry 279, 14447-14455.
213. Puri, S., Li, R., Ruszaj, D., Tati, S., and Edgerton, M. (2015) Iron binding modulates candidacidal properties of salivary histatin 5. Journal of Dental Research 94, 201-208.
214. Hayes, B. M., Anderson, M. A., Traven, A., van der Weerden, N. L., and Bleackley, M. R. (2014) Activation of stress signalling pathways enhances tolerance of fungi to chemical fungicides and antifungal proteins. Cellular and Molecular Life Sciences 71, 2651-2666.
215. Vylkova, S., Jang, W. S., Li, W., Nayyar, N., and Edgerton, M. (2007) Histatin 5 initiates osmotic stress response in Candida albicans via activation of the Hog1 mitogen-activated protein kinase pathway. Eukaryotic Cell 6, 1876-1888.
216. Li, R., Puri, S., Tati, S., Cullen, P. J., and Edgerton, M. (2015) Candida albicans Cek1 mitogen-activated protein kinase signaling enhances fungicidal activity of salivary histatin 5. Antimicrobial Agents and Chemotherapy 59, 3460-3468.
217. Bochenska, O., Rapala-Kozik, M., Wolak, N., Aoki, W., Ueda, M., and Kozik, A. (2016) The action of ten secreted aspartic proteases of pathogenic yeast Candida albicans on major human salivary antimicrobial peptide, histatin 5. Acta Biochimica Polonica 63, 403-410.
218. Szafranski-Schneider, E., Swidergall, M., Cottier, F., Tielker, D., Roman, E., Pla, J., and Ernst, J. F. (2012) Msb2 shedding protects Candida albicans against antimicrobial peptides. PLOS Pathogens 8, e1002501.
219. Puri, S., Friedman, J., Saraswat, D., Kumar, R., Li, R., Ruszaj, D., and Edgerton, M. (2015) Candida albicans shed Msb2 and host mucins affect the candidacidal activity of salivary Hst 5. Pathogens 4, 752-763.
220. Rothstein, D. M., Spacciapoli, P., Tran, L. T., Xu, T., Roberts, F. D., Dalla Serra, M., Buxton, D. K., Oppenheim, F. G., and Friden, P. (2001) Anticandida activity is retained in P-113, a 12-amino-acid fragment of histatin 5. Antimicrob Agents Chemother 45, 1367-1373.
221. Driscoll, J., Duan, C., Zuo, Y., Xu, T., Troxler, R., and Oppenheim, F. G. (1996) Candidacidal activity of human salivary histatin recombinant variants produced by site-directed mutagenesis. Gene 177, 29-34.
222. Tsai, H., Raj, P. A., and Bobek, L. A. (1996) Candidacidal activity of recombinant human salivary histatin-5 and variants. Infection and immunity 64, 5000-5007.
223. Jang, W. S., Li, X. S., Sun, J. N., and Edgerton, M. (2008) The P-113 fragment of histatin 5 requires a specific peptide sequence for intracellular translocation in Candida albicans, which is independent of cell wall binding. Antimicrobial Agents and Chemotherapy 52, 497-504.
224. Kulon, K., Valensin, D., Kamysz, W., Valensin, G., Nadolski, P., Porciatti, E., Gaggelli, E., and Kozlowski, H. (2008) The His-His sequence of the antimicrobial peptide demegen P-113 makes it very attractive ligand for Cu2+. Journal of Inorganic Biochemistry 102, 960-972.
225. MacPhee, C. E., Perugini, M. A., Sawyer, W. H., and Howlett, G. J. (1997) Trifluoroethanol induces the self-association of specific amphipathic peptides. FEBS Letters 416, 265-268.
226. Giacometti, A., Cirioni, O., Kamysz, W., D'Amato, G., Silvestri, C., Del Prete, M. S., Licci, A., Riva, A., Lukasiak, J., and Scalise, G. (2005) In vitro activity of the histatin derivative P-113 against multidrug-resistant pathogens responsible for pneumonia in immunocompromised patients. Antimicrobial Agents and Chemotherapy 49, 1249-1252.
227. Sajjan, U. S., Tran, L. T., Sole, N., Rovaldi, C., Akiyama, A., Friden, P. M., Forstner, J. F., and Rothstein, D. M. (2001) P-113D, an antimicrobial peptide active against Pseudomonas aeruginosa, retains activity in the presence of sputum from cystic fibrosis patients. Antimicrobial Agents and Chemotherapy 45, 3437-3444.
228. Yu, H. Y., Tu, C. H., Yip, B. S., Chen, H. L., Cheng, H. T., Huang, K. C., Lo, H. J., and Cheng, J. W. (2011) Easy strategy to increase salt resistance of antimicrobial peptides. Antimicrobial Agents and Chemotherapy 55, 4918-4921.
229. Han, J., Jyoti, M. A., Song, H. Y., and Jang, W. S. (2016) Antifungal activity and action mechanism of histatin 5-halocidin hybrid peptides against Candida ssp. PLOS One 11, e0150196.
230. Wanmakok, M., Orrapin, S., Intorasoot, A., and Intorasoot, S. (2018) Expression in Escherichia coli of novel recombinant hybrid antimicrobial peptide AL32-P113 with enhanced antimicrobial activity in vitro. Gene 671, 1-9.
231. Lin, G. Y., Chen, H. F., Xue, Y. P., Yeh, Y. C., Chen, C. L., Liu, M. S., Cheng, W. C., and Lan, C. Y. (2016) The Antimicrobial peptides P-113Du and P-113Tri function against Candida albicans. Antimicrobial Agents and Chemotherapy 60, 6369-6373.
232. Clinical Laboratory Standards Institute. (2012) Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; Approved Standard—Ninth Edition, M07-A9. Clinical and Laboratory Standards Institute, Wayne, PA.
233. Riss, T. L., Moravec, R. A., Niles, A. L., Duellman, S., Benink, H. A., Worzella, T. J., and Minor, L. (2016) Cell viability assays. in Assay Guidance Manual, Eli Lilly & Company and the National Center for Advancing Translational Sciences.
234. Makrantoni, V., Dennison, P., Stark, M. J., and Coote, P. J. (2007) A novel role for the yeast protein kinase Dbf2p in vacuolar H+-ATPase function and sorbic acid stress tolerance. Microbiology 153, 4016-4026.
235. Tsai, P. W., Yang, C. Y., Chang, H. T., and Lan, C. Y. (2011) Human antimicrobial peptide LL-37 inhibits adhesion of Candida albicans by interacting with yeast cell-wall carbohydrates. PLOS One 6, e17755.
236. Clinical Laboratory Standards Institute. (2008) Reference method for broth dilution antifungal susceptibility testing of yeasts; Approved Standard—Third Edition, M27-A3.
237. Baranauskiene, L., Petrikaite, V., Matuliene, J., and Matulis, D. (2009) Titration calorimetry standards and the precision of isothermal titration calorimetry data. International Journal of Molecular Sciences 10, 2752-2762.
238. Chang, C. F., Pan, J. F., Lin, C. N., Wu, I. L., Wong, C. H., and Lin, C. H. (2011) Rapid characterization of sugar-binding specificity by in-solution proximity binding with photosensitizers. Glycobiology 21, 895-902.
239. Yount, N. Y., and Yeaman, M. R. (2004) Multidimensional signatures in antimicrobial peptides. Proceedings of the National Academy of Sciences of the United States of America 101, 7363-7368.
240. Yin, L. M., Edwards, M. A., Li, J., Yip, C. M., and Deber, C. M. (2012) Roles of hydrophobicity and charge distribution of cationic antimicrobial peptides in peptide-membrane interactions. The Journal of Biological Chemistry 287, 7738-7745.
241. Pathak, N., Salas-Auvert, R., Ruche, G., Janna, M. H., McCarthy, D., and Harrison, R. G. (1995) Comparison of the effects of hydrophobicity, amphiphilicity, and alpha-helicity on the activities of antimicrobial peptides. Proteins 22, 182-186.
242. Holzwarth, G., and Doty, P. (1965) The ultraviolet circular dichroism of polypeptides. Journal of the American Chemical Society 87, 218-228.
243. Micsonai, A., Wien, F., Kernya, L., Lee, Y. H., Goto, Y., Refregiers, M., and Kardos, J. (2015) Accurate secondary structure prediction and fold recognition for circular dichroism spectroscopy. Proceedings of the National Academy of Sciences of the United States of America 112, E3095-3103.
244. Bowman, S. M., and Free, S. J. (2006) The structure and synthesis of the fungal cell wall. BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology 28, 799-808.
245. Hall, R. A., and Gow, N. A. (2013) Mannosylation in Candida albicans: role in cell wall function and immune recognition. Molecular Microbiology 90, 1147-1161.
246. Sherrington, S. L., Sorsby, E., Mahtey, N., Kumwenda, P., Lenardon, M. D., Brown, I., Ballou, E. R., MacCallum, D. M., and Hall, R. A. (2017) Adaptation of Candida albicans to environmental pH induces cell wall remodelling and enhances innate immune recognition. PLOS Pathogens 13, e1006403.
247. Noble, S. M., and Johnson, A. D. (2005) Strains and strategies for large-scale gene deletion studies of the diploid human fungal pathogen Candida albicans. Eukaryotic Cell 4, 298-309.
248. Noble, S. M., French, S., Kohn, L. A., Chen, V., and Johnson, A. D. (2010) Systematic screens of a Candida albicans homozygous deletion library decouple morphogenetic switching and pathogenicity. Nature Genetics 42, 590-598.
249. Bates, S., MacCallum, D. M., Bertram, G., Munro, C. A., Hughes, H. B., Buurman, E. T., Brown, A. J., Odds, F. C., and Gow, N. A. (2005) Candida albicans Pmr1p, a secretory pathway P-type Ca2+/Mn2+-ATPase, is required for glycosylation and virulence. The Journal of Biological Chemistry 280, 23408-23415.
250. Harris, M., Mora-Montes, H. M., Gow, N. A., and Coote, P. J. (2009) Loss of mannosylphosphate from Candida albicans cell wall proteins results in enhanced resistance to the inhibitory effect of a cationic antimicrobial peptide via reduced peptide binding to the cell surface. Microbiology 155, 1058-1070.
251. Ibeas, J. I., Lee, H., Damsz, B., Prasad, D. T., Pardo, J. M., Hasegawa, P. M., Bressan, R. A., and Narasimhan, M. L. (2000) Fungal cell wall phosphomannans facilitate the toxic activity of a plant PR-5 protein. Plant Journal 23, 375-383.
252. Koo, J. C., Lee, B., Young, M. E., Koo, S. C., Cooper, J. A., Baek, D., Lim, C. O., Lee, S. Y., Yun, D. J., and Cho, M. J. (2004) Pn-AMP1, a plant defense protein, induces actin depolarization in yeasts. Plant and Cell Physiology 45, 1669-1680.
253. Matsuzaki, K. (2019) Membrane permeabilization mechanisms. Advances in Experimental Medicine and Biology 1117, 9-16.
254. Gyurko, C., Lendenmann, U., Helmerhorst, E. J., Troxler, R. F., and Oppenheim, F. G. (2001) Killing of Candida albicans by histatin 5: cellular uptake and energy requirement. Antonie Van Leeuwenhoek 79, 297-309.
255. She, X., Khamooshi, K., Gao, Y., Shen, Y., Lv, Y., Calderone, R., Fonzi, W., Liu, W., and Li, D. (2015) Fungal-specific subunits of the Candida albicans mitochondrial complex I drive diverse cell functions including cell wall synthesis. Cellular Microbiology 17, 1350-1364.
256. Li, D., She, X., and Calderone, R. (2016) Functional diversity of complex I subunits in Candida albicans mitochondria. Current genetics 62, 87-95.
257. Li, L., Naseem, S., Sharma, S., and Konopka, J. B. (2015) Flavodoxin-like proteins protect Candida albicans from oxidative stress and promote virulence. PLOS Pathogens 11, e1005147.
258. Dwyer, D. J., Belenky, P. A., Yang, J. H., MacDonald, I. C., Martell, J. D., Takahashi, N., Chan, C. T., Lobritz, M. A., Braff, D., Schwarz, E. G., Ye, J. D., Pati, M., Vercruysse, M., Ralifo, P. S., Allison, K. R., Khalil, A. S., Ting, A. Y., Walker, G. C., and Collins, J. J. (2014) Antibiotics induce redox-related physiological alterations as part of their lethality. Proceedings of the National Academy of Sciences of the United States of America 111, E2100-2109.
259. Veerman, E. C., Nazmi, K., Van't Hof, W., Bolscher, J. G., Den Hertog, A. L., and Nieuw Amerongen, A. V. (2004) Reactive oxygen species play no role in the candidacidal activity of the salivary antimicrobial peptide histatin 5. The Biochemical journal 381, 447-452.
260. Wunder, D., Dong, J., Baev, D., and Edgerton, M. (2004) Human salivary histatin 5 fungicidal action does not induce programmed cell death pathways in Candida albicans. Antimicrobial Agents and Chemotherapy 48, 110-115.
261. Puri, S., and Edgerton, M. (2014) How does it kill?: understanding the candidacidal mechanism of salivary histatin 5. Eukaryotic cell 13, 958-964.
262. Khurshid, Z., Najeeb, S., Mali, M., Moin, S. F., Raza, S. Q., Zohaib, S., Sefat, F., and Zafar, M. S. (2017) Histatin peptides: Pharmacological functions and their applications in dentistry. Saudi Pharmaceutical Journal 25, 25-31.
263. Ma, Q. Q., Lv, Y. F., Gu, Y., Dong, N., Li, D. S., and Shan, A. S. (2013) Rational design of cationic antimicrobial peptides by the tandem of leucine-rich repeat. Amino Acids 44, 1215-1224.
264. Roncevic, T., Gajski, G., Ilic, N., Goic-Barisic, I., Tonkic, M., Zoranic, L., Simunic, J., Benincasa, M., Mijakovic, M., Tossi, A., and Juretic, D. (2017) PGLa-H tandem-repeat peptides active against multidrug resistant clinical bacterial isolates. Biochimica et biophysica acta. Biomembranes 1859, 228-237.
265. Dielbandhoesing, S. K., Zhang, H., Caro, L. H., van der Vaart, J. M., Klis, F. M., Verrips, C. T., and Brul, S. (1998) Specific cell wall proteins confer resistance to nisin upon yeast cells. Applied and environmental microbiology 64, 4047-4052.
266. Peschel, A., Otto, M., Jack, R. W., Kalbacher, H., Jung, G., and Gotz, F. (1999) Inactivation of the dlt operon in Staphylococcus aureus confers sensitivity to defensins, protegrins, and other antimicrobial peptides. The Journal of Biological Chemistry 274, 8405-8410.
267. Peschel, A. (2002) How do bacteria resist human antimicrobial peptides? Trends in Microbiology 10, 179-186.
268. Sem, X., Le, G. T., Tan, A. S., Tso, G., Yurieva, M., Liao, W. W., Lum, J., Srinivasan, K. G., Poidinger, M., Zolezzi, F., and Pavelka, N. (2016) beta-glucan exposure on the fungal cell wall tightly correlates with competitive fitness of Candida species in the mouse gastrointestinal tract. Frontiers in Cellular and Infection Microbiology 6, 186.
269. Mueller, A., Raptis, J., Rice, P. J., Kalbfleisch, J. H., Stout, R. D., Ensley, H. E., Browder, W., and Williams, D. L. (2000) The influence of glucan polymer structure and solution conformation on binding to (1-->3)-beta-D-glucan receptors in a human monocyte-like cell line. Glycobiology 10, 339-346.
270. Chaffin, W. L., Lopez-Ribot, J. L., Casanova, M., Gozalbo, D., and Martinez, J. P. (1998) Cell wall and secreted proteins of Candida albicans: identification, function, and expression. Microbiology and Molecular Biology Reviews 62, 130-180.
271. Sandini, S., La Valle, R., De Bernardis, F., Macri, C., and Cassone, A. (2007) The 65 kDa mannoprotein gene of Candida albicans encodes a putative beta-glucanase adhesin required for hyphal morphogenesis and experimental pathogenicity. Cellular Microbiology 9, 1223-1238.
272. Mariano, F. S., Campanelli, A. P., Nociti, F. H., Jr., Mattos-Graner, R. O., and Goncalves, R. B. (2012) Antimicrobial peptides and nitric oxide production by neutrophils from periodontitis subjects. Brazilian Journal of Medical and Biological Research 45, 1017-1024.
273. Le, C. F., Fang, C. M., and Sekaran, S. D. (2017) Intracellular targeting mechanisms by antimicrobial peptides. Antimicrobial Agents and Chemotherapy 61, e02340-16.
274. Madani, F., Lindberg, S., Langel, U., Futaki, S., and Gräslund, A. (2011) Mechanisms of cellular uptake of cell-penetrating peptides. Journal of Biophysics 2011, 414729-414729.
275. Dickinson, B. C., and Chang, C. J. (2011) Chemistry and biology of reactive oxygen species in signaling or stress responses. Nature Chemical Biology 7, 504-511.
276. Helmerhorst, E. J., Troxler, R. F., and Oppenheim, F. G. (2001) The human salivary peptide histatin 5 exerts its antifungal activity through the formation of reactive oxygen species. Proceedings of the National Academy of Sciences of the United States of America 98, 14637-14642.
277. Gyurko, C., Lendenmann, U., Troxler, R. F., and Oppenheim, F. G. (2000) Candida albicans mutants deficient in respiration are resistant to the small cationic salivary antimicrobial peptide histatin 5. Antimicrobial Agents and Chemotherapy 44, 348-354.
278. Zorov, D. B., Juhaszova, M., and Sollott, S. J. (2014) Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiological Reviews 94, 909-950.
279. Ramsay, R. R., and Singer, T. P. (1992) Relation of superoxide generation and lipid peroxidation to the inhibition of NADH-Q oxidoreductase by rotenone, piericidin A, and MPP+. Biochemical and Biophysical Research Communications 189, 47-52.
280. Perrone, G. G., Tan, S. X., and Dawes, I. W. (2008) Reactive oxygen species and yeast apoptosis. Biochimica et Biophysica Acta 1783, 1354-1368.
281. Karkowska-Kuleta, J., and Kozik, A. (2015) Cell wall proteome of pathogenic fungi. Acta Biochimica Polonica 62, 339-351.
282. Chaffin, W. L. (2008) Candida albicans cell wall proteins. Microbiology and Molecular Biology Reviews 72, 495-544.
283. Brogden, K. A. (2005) Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nature Reviews Microbiology 3, 238-250.
284. Zhu, H., Bilgin, M., Bangham, R., Hall, D., Casamayor, A., Bertone, P., Lan, N., Jansen, R., Bidlingmaier, S., Houfek, T., Mitchell, T., Miller, P., Dean, R. A., Gerstein, M., and Snyder, M. (2001) Global analysis of protein activities using proteome chips. Science 293, 2101-2105.
285. Wheeler, R. T., and Fink, G. R. (2006) A drug-sensitive genetic network masks fungi from the immune system. PLOS Pathogens 2, e35.
286. Martinez-Esparza, M., Sarazin, A., Jouy, N., Poulain, D., and Jouault, T. (2006) Comparative analysis of cell wall surface glycan expression in Candida albicans and Saccharomyces cerevisiae yeasts by flow cytometry. Journal of Immunological Methods 314, 90-102.
287. Wheeler, R. T., Kombe, D., Agarwala, S. D., and Fink, G. R. (2008) Dynamic, morphotype-specific Candida albicans beta-glucan exposure during infection and drug treatment. PLOS Pathogens 4, e1000227.
288. Tsai, P.-W. W., Cheng, Y.-L. L., Hsieh, W.-P. P., and Lan, C.-Y. Y. (2014) Responses of Candida albicans to the human antimicrobial peptide LL-37. Journal of Microbiology 52, 581-589.
289. François, J. (2006) A simple method for quantitative determination of polysaccharides in fungal cell walls. Nature protocols 1, 2995-3000.
290. Vylkova, S., Jang, W. S., Li, W., Nayyar, N., and Edgerton, M. (2007) Histatin 5 initiates osmotic stress response in Candida albicans via activation of the Hog1 mitogen-activated protein kinase pathway. Eukaryotic Cell 10, 1876-88.
291. Delgado-Silva, Y., Vaz, C., Carvalho-Pereira, J., Carneiro, C., Nogueira, E., Correia, A., Carreto, L., Silva, S., Faustino, A., Pais, C., Oliveira, R., and Sampaio, P. (2014) Participation of Candida albicans transcription factor RLM1 in cell wall biogenesis and virulence. PLOS One 9, e86270.
292. Tsao, C. C., Chen, Y. T., and Lan, C. Y. (2009) A small G protein Rhb1 and a GTPase-activating protein Tsc2 involved in nitrogen starvation-induced morphogenesis and cell wall integrity of Candida albicans. Fungal Genetics and Biology 46, 126-136.
293. Belenky, P., Camacho, D., and Collins, J. J. (2013) Fungicidal drugs induce a common oxidative-damage cellular death pathway. Cell Reports 3, 350-358.
294. Chen, X., Ren, B., Chen, M., Liu, M. X., Ren, W., Wang, Q. X., Zhang, L. X., and Yan, G. Y. (2014) ASDCD: antifungal synergistic drug combination database. PLOS One 9, e86499.
295. De Cremer, K., Lanckacker, E., Cools, T. L., Bax, M., De Brucker, K., Cos, P., Cammue, B. P., and Thevissen, K. (2015) Artemisinins, new miconazole potentiators resulting in increased activity against Candida albicans biofilms. Antimicrobial Agents and Chemotherapy 59, 421-426.
296. Wittekind, M., and Schuch, R. (2016) Cell wall hydrolases and antibiotics: exploiting synergy to create efficacious new antimicrobial treatments. Current Opinion in Microbiology 33, 18-24.
297. Callewaert, L., and Michiels, C. W. (2010) Lysozymes in the animal kingdom. Journal of Biosciences 35, 127-160.
298. Samaranayake, Y. H., Samaranayake, L. P., Wu, P. C., and So, M. (1997) The antifungal effect of lactoferrin and lysozyme on Candida krusei and Candida albicans. APMIS 105, 875-883.
299. Samaranayake, Y. H., Cheung, B. P., Parahitiyawa, N., Seneviratne, C. J., Yau, J. Y., Yeung, K. W., and Samaranayake, L. P. (2009) Synergistic activity of lysozyme and antifungal agents against Candida albicans biofilms on denture acrylic surfaces. Archives of Oral Biology 54, 115-126.
300. Gillum, A. M., Tsay, E. Y., and Kirsch, D. R. (1984) Isolation of the Candida albicans gene for orotidine-5'-phosphate decarboxylase by complementation of S. cerevisiae ura3 and E. coli pyrF mutations. Molecular & General Genetics 198, 179-182.
301. Fonzi, W. A., and Irwin, M. Y. (1993) Isogenic strain construction and gene mapping in Candida albicans. Genetics 134, 717-728.
302. Prill, S. K., Klinkert, B., Timpel, C., Gale, C. A., Schroppel, K., and Ernst, J. F. (2005) PMT family of Candida albicans: five protein mannosyltransferase isoforms affect growth, morphogenesis and antifungal resistance. Molecular Microbiology 55, 546-560.
303. Brand, A., MacCallum, D. M., Brown, A. J., Gow, N. A., and Odds, F. C. (2004) Ectopic expression of URA3 can influence the virulence phenotypes and proteome of Candida albicans but can be overcome by targeted reintegration of URA3 at the RPS10 locus. Eukaryotic Cell 3, 900-909.
304. Ng, S. K., Huang, Y. T., Lee, Y. C., Low, E. L., Chiu, C. H., Chen, S. L., Mao, L. C., and Chang, M. D. (2014) A recombinant horseshoe crab plasma lectin recognizes specific pathogen-associated molecular patterns of bacteria through rhamnose. PLOS One 9, e115296.
305. Le Pendu J, Marionneau S, Cailleau-Thomas A, Rocher J, Le Moullac-Vaidye B, Clement M. (2001) ABH and Lewis histo-blood group antigens in cancer. Acta Pathologica, Microbiologica, et Immunologica Scandinavica 109, 9-31.