Activity of Metal-Azole Complexes Against Biofilms of Candida albicans and Candida glabrata

Author(s): Livia D. Pereira, Taissa Vila, Luana P. Borba-Santos, Wanderley de Souza, Maribel Navarro, Sonia Rozental*.

Journal Name: Current Pharmaceutical Design

Volume 26 , Issue 14 , 2020

Become EABM
Become Reviewer


Background: Onychomycosis is a chronic nail infection caused by fungi frequently resistant to antifungal treatments. Recalcitrance in nail infections is a result of reduced antifungal penetration due to biofilm formation, combined with poor patient compliance with the treatment, which can be as long as 18 months.

Objective: Metal-drug complexation is a widely used strategy to increase drug efficacy. Therefore, the aim of this work was to evaluate the antifungal and anti-biofilm activity of several metal-azole complexes against Candida albicans and Candida glabrata.

Methods: Susceptibility assays and scanning electron microscopy were performed to determine the anti-biofilm activity of eight metal-azole complexes in vitro and ex-vivo, using human nail fragments.

Results: In vitro susceptibility assays showed that complexation of both Au(I) and Zn(II) to clotrimazole and ketoconazole improved the anti-biofilm activity compared to the azole alone. Using an ex-vivo model of biofilm formation on fragments of human nails, we also demonstrate the improved efficacy of metal-azole complexes against biofilms of C. albicans and C. glabrata that resembles the onychomycosis structure. Noteworthy, biofilms of C. glabrata were more susceptible to the optimized complexes than those of C. albicans.

Conclusion: In conclusion, metal-azole complexes used in this work show promising anti-biofilm activity and further clinical studies should confirm its potential for the treatment of Candida-associated onychomycosis.

Keywords: Candida albicans, Candida glabrata, onychomycosis, antifungals, biofilms, metal-complexes, drug optimization.

Baswan S, Kasting GB, Li SK, et al. Understanding the formidable nail barrier: A review of the nail microstructure, composition and diseases. Mycoses 2017; 60(5): 284-95.
[] [PMID: 28098391]
Gupta AK, Versteeg SG, Shear NH. Onychomycosis in the 21st century: an update on diagnosis, epidemiology, and treatment. J Cutan Med Surg 2017; 21(6): 525-39.
[] [PMID: 28639462]
Christenson JK, Peterson GM, Naunton M, et al. Challenges and Opportunities in the Management of Onychomycosis. J Fungi (Basel) 2018; 4(3) E87
[] [PMID: 30042327]
Vlahovic TC. Onychomycosis: evaluation, treatment options, managing recurrence, and patient outcomes. Clin Podiatr Med Surg 2016; 33(3): 305-18.
[] [PMID: 27215153]
Brilhante RS, Cordeiro RA, Medrano DJ, et al. Onychomycosis in Ceará (Northeast Brazil): epidemiological and laboratory aspects. Mem Inst Oswaldo Cruz 2005; 100(2): 131-5.
[] [PMID: 16021299]
Godoy-Martinez P, Nunes FG, Tomimori-Yamashita J, et al. Onychomycosis in São Paulo, Brazil. Mycopathologia 2009; 168(3): 111-6.
[] [PMID: 19424818]
Manzano-Gayosso P, Méndez-Tovar LJ, Arenas R, et al. [Onychomycosis-causing yeasts in four Mexican dermatology centers and their antifungal susceptibility to azolic compounds]. Rev Iberoam Micol 2011; 28(1): 32-5.
[] [PMID: 21147249]
Halim I, El Kadioui F, Soussi Abdallaoui M. [Onychomycosis in Casablanca (Morocco)]. J Mycol Med 2013; 23(1): 9-14.
[] [PMID: 23287730]
Di Chiacchio N, Suarez MV, Madeira CL, Loureiro WR. An observational and descriptive study of the epidemiology of and therapeutic approach to onychomycosis in dermatology offices in Brazil. An Bras Dermatol 2013; 88(Suppl. 1): 3-11.
[PMID: 23539065]
Vila TVM, Rozental S, de Sá Guimarães CMD. A new model of in vitro fungal biofilms formed on human nail fragments allows reliable testing of laser and light therapies against onychomycosis. Lasers Med Sci 2015; 30(3): 1031-9.
[] [PMID: 25471266]
Nusbaum AG, Kirsner RS, Charles CA. Biofilms in dermatology. Skin Therapy Lett 2012; 17(7): 1-5.
[PMID: 22825648]
Donlan RM, Costerton JW. Biofilms: survival mechanisms of clinically relevant microorganisms. Clin Microbiol Rev 2002; 15(2): 167-93.
[] [PMID: 11932229]
Nobile CJ, Johnson AD. Candida albicans Biofilms and Human Disease. Annu Rev Microbiol 2015; 69: 71-92.
[] [PMID: 26488273]
Navarro M, Colmenares I, Correia H, et al. In vitro activities of transition metal derivatives of ketoconazole and clotrimazole against a wild type strain of Saccharomyces cerevisiae in absence or presence of human neutrophils. Arzneimittelforschung 2004; 54(11): 746-51.
[PMID: 15612615]
McCann M, Curran R, Ben-Shoshan M, et al. Silver(I) complexes of 9-anthracenecarboxylic acid and imidazoles: synthesis, structure and antimicrobial activity. Dalton Trans 2012; 41(21): 6516-27.
[] [PMID: 22476383]
Gagini T, Colina-Vegas L, Villarreal W, et al. Metal-azole fungistatic drug complexes as anti-Sporothrix spp. agents. New J Chem 2018; 42: 13641-50.
Foster KW, Ghannoum MA, Elewski BE. Epidemiologic surveillance of cutaneous fungal infection in the United States from 1999 to 2002. J Am Acad Dermatol 2004; 50(5): 748-52.
[] [PMID: 15097959]
Ghannoum MA, Hajjeh RA, Scher R, et al. A large-scale North American study of fungal isolates from nails: the frequency of onychomycosis, fungal distribution, and antifungal susceptibility patterns. J Am Acad Dermatol 2000; 43(4): 641-8.
[] [PMID: 11004620]
Midlej V, Rubim F, Villarreal W, et al. Zinc-clotrimazole complexes are effective against Trichomonas vaginalis. Parasitology 2019; 146(9): 1206-16.
[] [PMID: 31046845]
Pfaller M, Chaturvedi V, Espinel-Ingroff A, Ghannoum MA. Reference method for broth dilution antifungal susceptibility testing of yeasts: approved standard. 4th ed.. Wayne, PA 2017; p. M27.
Baillie GS, Douglas LJ. Matrix polymers of Candida biofilms and their possible role in biofilm resistance to antifungal agents. J Antimicrob Chemother 2000; 46(3): 397-403.
[] [PMID: 10980166]
Thomas J, Peterson GM, Christenson JK, Kosari S, Baby KE. Antifungal drug use for onychomycosis. Am J Ther 2019; 26(3): e388-96.
[] [PMID: 31082864]
Burkhart CN, Burkhart CG, Gupta AK. Dermatophytoma: Recalcitrance to treatment because of existence of fungal biofilm. J Am Acad Dermatol 2002; 47(4): 629-31.
[] [PMID: 12271316]
Gupta AK, Daigle D, Carviel JL. The role of biofilms in onychomycosis. J Am Acad Dermatol 2016; 74(6): 1241-6.
[] [PMID: 27012826]
Gupta AK, Foley KA. Evidence for biofilms in onychomycosis. G Ital Dermatol Venereol 2019; 154(1): 50-5.
[] [PMID: 29683287]
Navarro M, Gonzalo V. Metal-based antiparasitic therapeutics.trace metals and infectious diseases. In: Nriagu Jerome O, Skaar Eric P, Eds. . Strüngmann Forum Reports J Lupp.. Cambridge, MA: MIT Press 2017; pp. 161-72.
Simpson PV, Nagel C, Bruhn H, Schatzshneider U. Antibacterial and antiparasitic activity of manganese(I) tricarbonyl complexes with ketoconazole, miconazole, and clotrimazole ligands. Organometallics 2015; 34: 3809-15.
Colina-Vegas L, Dutra JL, Villarreal W, et al. Ru(II)/clotrimazole/diphenylphosphine/bipyridine complexes: Interaction with DNA, BSA and biological potential against tumor cell lines and Mycobacterium tuberculosis. J Inorg Biochem 2016; 162: 135-45.
[] [PMID: 27383651]
Tsui C, Kong EF, Jabra-Rizk MA. Pathogenesis of Candida albicans biofilm. Pathog Dis 2016; 74(4) ftw018
[] [PMID: 26960943]
Ramage G, Wickes BL, Lopez-Ribot JL. Biofilms of Candida albicans and their associated resistance to antifungal agents. Am Clin Lab 2001; 20(7): 42-4.
[PMID: 11570274]
Kuhn DM, George T, Chandra J, Mukherjee PK, Ghannoum MA. Antifungal susceptibility of Candida biofilms: unique efficacy of amphotericin B lipid formulations and echinocandins. Antimicrob Agents Chemother 2002; 46(6): 1773-80.
[] [PMID: 12019089]
Glöckner A, Cornely OA. Candida glabrata--unique features and challenges in the clinical management of invasive infections. Mycoses 2015; 58(8): 445-50.
[] [PMID: 26207423]
Galocha M, Pais P, Cavalheiro M, Pereira D, Viana R, Teixeira MC. Divergent approaches to virulence in C. albicans and C. glabrata: two sides of the same coin. Int J Mol Sci 2019; 20(9) E2345
[] [PMID: 31083555]
Silva S, Henriques M, Martins A, Oliveira R, Williams D, Azeredo J. Biofilms of non-Candida albicans Candida species: quantification, structure and matrix composition. Med Mycol 2009; 47(7): 681-9.
[] [PMID: 19888800]
Sasani E, Khodavaisy S, Agha Kuchak Afshari S, Darabian S, Aala F, Rezaie S. Pseudohyphae formation in Candida glabrata due to CO2 exposure. Curr Med Mycol 2016; 2(4): 49-52.
[] [PMID: 28959796]
Calcagno AM, Bignell E, Rogers TR, Jones MD, Mühlschlegel FA, Haynes K. Candida glabrata Ste11 is involved in adaptation to hypertonic stress, maintenance of wild-type levels of filamentation and plays a role in virulence. Med Mycol 2005; 43(4): 355-64.
[] [PMID: 16110782]
Csank C, Haynes K. Candida glabrata displays pseudohyphal growth. FEMS Microbiol Lett 2000; 189(1): 115-20.
[] [PMID: 10913876]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2020
Page: [1524 - 1531]
Pages: 8
DOI: 10.2174/1381612826666200217120321
Price: $65

Article Metrics

PDF: 12
PRC: 1