Phenotypic Investigation of Virulence Factors, Susceptibility to Ceragenins, and the Impact of Biofilm Formation on Drug Efficacy in Candida auris Isolates from Türkiye
Abstract
:1. Introduction
2. Materials and Methods
2.1. Isolates and Growth Conditions
2.2. Virulence Factors
2.2.1. Proteinase Activity
2.2.2. Phospholipase Activity
2.2.3. Esterase Activity
2.2.4. Hemolysin Production
2.2.5. Evaluation of Virulence Factors
2.2.6. Biofilm Formation
2.3. Antifungal Susceptibility Tests
2.4. Antibiofilm Activity
3. Results
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Ahmad, S.; Alfouzan, W. Candida auris: Epidemiology, Diagnosis, Pathogenesis, Antifungal Susceptibility, and Infection Control Measures to Combat the Spread of Infections in Healthcare Facilities. Microorganisms 2021, 9, 807. [Google Scholar] [CrossRef]
- Satoh, K.; Makimura, K.; Hasumi, Y.; Nishiyama, Y.; Uchida, K.; Yamaguchi, H. Candida auris sp. nov., a novel ascomycetous yeast isolated from the external ear canal of an inpatient in a Japanese hospital. Microbiol. Immunol. 2009, 53, 41–44. [Google Scholar] [CrossRef]
- Hu, S.; Zhu, F.; Jiang, W.; Wang, Y.; Quan, Y.; Zhang, G.; Gu, F.; Yang, Y. Retrospective Analysis of the Clinical Characteristics of Candida auris Infection Worldwide From 2009 to 2020. Front. Microbiol. 2021, 12, 658329. [Google Scholar] [CrossRef]
- Chow, N.A.; de Groot, T.; Badali, H.; Abastabar, M.; Chiller, T.M.; Meis, J.F. Potential Fifth Clade of Candida auris, Iran, 2018. Emerg. Infect Dis. 2019, 25, 1780–1781. [Google Scholar] [CrossRef] [PubMed]
- Kohlenberg, A.; Monnet, D.L.; Plachouras, D. Increasing number of cases and outbreaks caused by Candida auris in the EU/EEA, 2020 to 2021. Eurosurveillance 2022, 27, 2200846. [Google Scholar] [CrossRef]
- Lyman, M.; Forsberg, K.; Sexton, D.J.; Chow, N.A.; Lockhart, S.R.; Jackson, B.R.; Chiller, T. Worsening Spread of Candida auris in the United States, 2019 to 2021. Ann. Intern. Med. 2023, 176, 489–495. [Google Scholar] [CrossRef] [PubMed]
- Kurt, A.F.; Kuskucu, M.A.; Balkan, I.I.; Baris, A.; Yazgan, Z.; Serife Oz, A.; Tosun, A.I.; Mete, B.; Tabak, F.; Aygun, G. Candida auris Fungemia and a local spread taken under control with infection control measures: First report from Turkey. Indian J. Med. Microbiol. 2021, 39, 228–230. [Google Scholar] [CrossRef] [PubMed]
- de Cássia Orlandi Sardi, J.; Silva, D.R.; Soares Mendes-Giannini, M.J.; Rosalen, P.L. Candida auris: Epidemiology, risk factors, virulence, resistance, and therapeutic options. Microb. Pathog. 2018, 125, 116–121. [Google Scholar] [CrossRef]
- Rayens, E.; Norris, K.A. Prevalence and Healthcare Burden of Fungal Infections in the United States, 2018. Open Forum Infect. Dis. 2022, 9, ofab593. [Google Scholar] [CrossRef]
- CDC. Candida auris. Available online: https://www.cdc.gov/fungal/candida-auris/index.html (accessed on 6 September 2023).
- Horton, M.V.; Nett, J.E. Candida auris infection and biofilm formation: Going beyond the surface. Curr. Clin. Microbiol. Rep. 2020, 7, 51–56. [Google Scholar] [CrossRef]
- Sears, D.; Schwartz, B.S. Candida auris: An emerging multidrug-resistant pathogen. Int. J. Infect. Dis. 2017, 63, 95–98. [Google Scholar] [CrossRef] [PubMed]
- Hashemi, M.M.; Rovig, J.; Weber, S.; Hilton, B.; Forouzan, M.M.; Savage, P.B. Susceptibility of Colistin-Resistant, Gram-Negative Bacteria to Antimicrobial Peptides and Ceragenins. Antimicrob. Agents Chemother. 2017, 61, e00292-17. [Google Scholar] [CrossRef] [PubMed]
- Oyardi, O.; Eltimur, T.; Demir, E.S.; Alkan, B.; Savage, P.B.; Akcali, A.; Bozkurt-Guzel, C. Antibacterial and Antibiofilm Activities of Ceragenins Alone and in Combination with Levofloxacin Against Multidrug Resistant Myroides spp. Clinical Isolates from Patients with Urinary Tract Infections. Curr. Microbiol. 2023, 80, 210. [Google Scholar] [CrossRef] [PubMed]
- Surel, U.; Niemirowicz, K.; Marzec, M.T.; Savage, P.B.; Bucki, R.; Roth, D.B.; Burton, G.W. Ceragenins—A new weapon to fight multidrug resistant bacterial infections/Cerageniny—Nowe perspektywy w zwalczaniu infekcji wywołanych przez wielooporne szczepy bakteryjne. Med. Stud./Studia Medyczne 2014, 30, 207–213. [Google Scholar] [CrossRef]
- Hacioglu, M.; Guzel, C.B.; Savage, P.B.; Tan, A.S.B. Antifungal susceptibilities, in vitro production of virulence factors and activities of ceragenins against Candida spp. isolated from vulvovaginal candidiasis. Med. Mycol. 2019, 57, 291–299. [Google Scholar] [CrossRef]
- Hacioglu, M.; Oyardi, O.; Bozkurt-Guzel, C.; Savage, P.B. Antibiofilm activities of ceragenins and antimicrobial peptides against fungal-bacterial mono and multispecies biofilms. J. Antibiot. 2020, 73, 455–462. [Google Scholar] [CrossRef]
- Durnaś, B.; Wnorowska, U.; Pogoda, K.; Deptuła, P.; Wątek, M.; Piktel, E.; Głuszek, S.; Gu, X.; Savage, P.B.; Niemirowicz, K.; et al. Candidacidal Activity of Selected Ceragenins and Human Cathelicidin LL-37 in Experimental Settings Mimicking Infection Sites. PLoS ONE 2016, 11, e0157242. [Google Scholar] [CrossRef]
- Hashemi, M.M.; Rovig, J.; Holden, B.S.; Taylor, M.F.; Weber, S.; Wilson, J.; Hilton, B.; Zaugg, A.L.; Ellis, S.W.; Yost, C.D.; et al. Ceragenins are active against drug-resistant Candida auris clinical isolates in planktonic and biofilm forms. J. Antimicrob. Chemother. 2018, 73, 1537–1545. [Google Scholar] [CrossRef]
- Aslan, M.; Turan, D.; Altunal, L.N.; Aksaray, S. Laboratuvarımızda izole edilen ilk C. auris olgusu. In Proceedings of the 6. Ulusal Klinik Mikrobiyoloji Hibrid Kongresi, Online, 20–24 October 2021; p. 026. [Google Scholar]
- Bölükbaşı, Y.; Erköse Genç, G.; Orhun, G.; Kuşkucu, M.A.; Çağatay, A.; Önel, M.; Öngen, B.; Ağaçfidan, A.; Esen, F.; Erturan, Z. [First Case of COVID-19 Positive Candida auris Fungemia in Turkey]. Mikrobiyoloji Bulteni 2021, 55, 648–655. [Google Scholar] [CrossRef]
- Kömeç, S.; Karabıçak, N.; Ceylan, A.N.; Gülmez, A.; Özalp, O. [Three Candida auris Case Reports from Istanbul, Turkey]. Mikrobiyoloji Bulteni 2021, 55, 452–460. [Google Scholar] [CrossRef]
- Teke, L.; Sargın Altunok, E.; Genç Moralar, D. The Second Case of Candida auris Candidemia from Turkey: An Impending Threat to the Global Health. Mediterr. J. Infect. Microb. Antimicrob. 2021, 10, 48. [Google Scholar] [CrossRef]
- Aoki, S.; Ito-Kuwa, S.; Nakamura, Y.; Masuhara, T. Comparative pathogenicity of a wild-type strain and respiratory mutants of Candida albicans in mice. Zentralbl Bakteriol 1990, 273, 332–343. [Google Scholar] [CrossRef] [PubMed]
- Price, M.F.; Wilkinson, I.D.; Gentry, L.O. Plate method for detection of phospholipase activity in Candida albicans. Sabouraudia 1982, 20, 7–14. [Google Scholar] [CrossRef] [PubMed]
- Slifkin, M. Tween 80 opacity test responses of various Candida species. J. Clin. Microbiol. 2000, 38, 4626–4628. [Google Scholar] [CrossRef]
- Manns, J.M.; Mosser, D.M.; Buckley, H.R. Production of a hemolytic factor by Candida albicans. Infect. Immun. 1994, 62, 5154–5156. [Google Scholar] [CrossRef] [PubMed]
- Mroczyńska, M.; Brillowska-Dąbrowska, A. Virulence of Clinical Candida Isolates. Pathogens 2021, 10, 466. [Google Scholar] [CrossRef]
- CLSI Document M27-A3; Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard—Third Edition. Clinical And Laboratory Standards Institute (CLSI): Wayne, PA, USA, 2008.
- Lai, X.Z.; Feng, Y.; Pollard, J.; Chin, J.N.; Rybak, M.J.; Bucki, R.; Epand, R.F.; Epand, R.M.; Savage, P.B. Ceragenins: Cholic acid-based mimics of antimicrobial peptides. Acc. Chem. Res. 2008, 41, 1233–1240. [Google Scholar] [CrossRef]
- Nouraei, H.; Jahromi, M.G.; Jahromi, L.R.; Zomorodian, K.; Pakshir, K. Potential Pathogenicity of Candida Species Isolated from Oral Cavity of Patients with Diabetes Mellitus. Biomed. Res. Int. 2021, 2021, 9982744. [Google Scholar] [CrossRef] [PubMed]
- Talapko, J.; Juzbašić, M.; Matijević, T.; Pustijanac, E.; Bekić, S.; Kotris, I.; Škrlec, I. Candida albicans—The Virulence Factors and Clinical Manifestations of Infection. J. Fungi 2021, 7, 70. [Google Scholar] [CrossRef]
- Czechowicz, P.; Nowicka, J.; Gościniak, G. Virulence Factors of Candida spp. and Host Immune Response Important in the Pathogenesis of Vulvovaginal Candidiasis. Int. J. Mol. Sci. 2022, 23, 15895. [Google Scholar] [CrossRef]
- Zhou, W.; Li, X.; Lin, Y.; Yan, W.; Jiang, S.; Huang, X.; Yang, X.; Qiao, D.; Li, N. A Comparative Transcriptome Between Anti-drug Sensitive and Resistant Candida auris in China. Front. Microbiol. 2021, 12, 708009. [Google Scholar] [CrossRef] [PubMed]
- Kumar, D.; Banerjee, T.; Pratap, C.B.; Tilak, R. Itraconazole-resistant Candida auris with phospholipase, proteinase and hemolysin activity from a case of vulvovaginitis. J. Infect. Dev. Ctries 2015, 9, 435–437. [Google Scholar] [CrossRef] [PubMed]
- Carvajal, S.K.; Alvarado, M.; Rodríguez, Y.M.; Parra-Giraldo, C.M.; Varón, C.; Morales-López, S.E.; Rodríguez, J.Y.; Gómez, B.L.; Escandón, P. Pathogenicity Assessment of Colombian Strains of Candida auris in the Galleria mellonella Invertebrate Model. J. Fungi 2021, 7, 401. [Google Scholar] [CrossRef] [PubMed]
- Shaban, S.; Patel, M.; Ahmad, A. Improved efficacy of antifungal drugs in combination with monoterpene phenols against Candida auris. Sci. Rep. 2020, 10, 1162. [Google Scholar] [CrossRef]
- Larkin, E.; Hager, C.; Chandra, J.; Mukherjee, P.K.; Retuerto, M.; Salem, I.; Long, L.; Isham, N.; Kovanda, L.; Borroto-Esoda, K.; et al. The Emerging Pathogen Candida auris: Growth Phenotype, Virulence Factors, Activity of Antifungals, and Effect of SCY-078, a Novel Glucan Synthesis Inhibitor, on Growth Morphology and Biofilm Formation. Antimicrob. Agents Chemother. 2017, 61, e02396-16. [Google Scholar] [CrossRef]
- Borman, A.M.; Szekely, A.; Johnson, E.M. Comparative Pathogenicity of United Kingdom Isolates of the Emerging Pathogen Candida auris and Other Key Pathogenic Candida Species. mSphere 2016, 1, e00189-16. [Google Scholar] [CrossRef]
- Yue, H.; Bing, J.; Zheng, Q.; Zhang, Y.; Hu, T.; Du, H.; Wang, H.; Huang, G. Filamentation in Candida auris, an emerging fungal pathogen of humans: Passage through the mammalian body induces a heritable phenotypic switch. Emerg. Microbes Infect. 2018, 7, 188. [Google Scholar] [CrossRef]
- Chowdhary, A.; Prakash, A.; Sharma, C.; Kordalewska, M.; Kumar, A.; Sarma, S.; Tarai, B.; Singh, A.; Upadhyaya, G.; Upadhyay, S.; et al. A multicentre study of antifungal susceptibility patterns among 350 Candida auris isolates (2009–17) in India: Role of the ERG11 and FKS1 genes in azole and echinocandin resistance. J. Antimicrob. Chemother. 2018, 73, 891–899. [Google Scholar] [CrossRef]
- Kilburn, S.; Innes, G.; Quinn, M.; Southwick, K.; Ostrowsky, B.; Greenko, J.A.; Lutterloh, E.; Greeley, R.; Magleby, R.; Chaturvedi, V.; et al. Antifungal Resistance Trends of Candida auris Clinical Isolates in New York and New Jersey from 2016 to 2020. Antimicrob. Agents Chemother. 2022, 66, e0224221. [Google Scholar] [CrossRef]
- Li, J.; Coste, A.T.; Liechti, M.; Bachmann, D.; Sanglard, D.; Lamoth, F. Novel ERG11 and TAC1b mutations associated with azole resistance in Candida auris. Antimicrob. Agents Chemother. 2023, 65, e02663-20. [Google Scholar] [CrossRef]
- Rybak, J.M.; Muñoz, J.F.; Barker, K.S.; Parker, J.E.; Esquivel, B.D.; Berkow, E.L.; Lockhart, S.R.; Gade, L.; Palmer, G.E.; White, T.C.; et al. Mutations in TAC1B: A Novel Genetic Determinant of Clinical Fluconazole Resistance in Candida auris. mBio 2020, 11, e00365-20. [Google Scholar] [CrossRef] [PubMed]
- Watkins, R.R.; Gowen, R.; Lionakis, M.S.; Ghannoum, M. Update on the Pathogenesis, Virulence, and Treatment of Candida auris. Pathog. Immun. 2022, 7, 46–65. [Google Scholar] [CrossRef] [PubMed]
- de Melo, C.C.; de Sousa, B.R.; da Costa, G.L.; Oliveira, M.M.E.; de Lima-Neto, R.G. Colonized patients by Candida auris: Third and largest outbreak in Brazil and impact of biofilm formation. Front. Cell. Infect. Microbiol. 2023, 13, 1033707. [Google Scholar] [CrossRef] [PubMed]
- Chatzimoschou, A.; Giampani, A.; Meis, J.F.; Roilides, E. Activities of nine antifungal agents against Candida auris biofilms. Mycoses 2021, 64, 381–384. [Google Scholar] [CrossRef]
- Romera, D.; Aguilera-Correa, J.J.; Gadea, I.; Viñuela-Sandoval, L.; García-Rodríguez, J.; Esteban, J. Candida auris: A comparison between planktonic and biofilm susceptibility to antifungal drugs. J. Med. Microbiol. 2019, 68, 1353–1358. [Google Scholar] [CrossRef]
- Atriwal, T.; Azeem, K.; Husain, F.M.; Hussain, A.; Khan, M.N.; Alajmi, M.F.; Abid, M. Mechanistic Understanding of Candida albicans Biofilm Formation and Approaches for Its Inhibition. Front. Microbiol. 2021, 12, 638609. [Google Scholar] [CrossRef]
Proteinase | Phospholipase | Esterase | Hemolysin | Biofilm Formation | ||||||
---|---|---|---|---|---|---|---|---|---|---|
Pz Value | Activity | Pz Value | Activity | Pz Value | Activity | Pz Value | Activity | OD595 | Activity | |
C. auris 1 | 0 | No activity | 0.830 | Weak | 0.761 | Weak | 0 | No activity | 0.451 | Strong |
C. auris 2 | 0 | No activity | 0.796 | Weak | 0.720 | Weak | 0 | No activity | 0.392 | Strong |
C. auris 3 | 0 | No activity | 0.776 | Weak | 0.700 | Weak | 0 | No activity | 0.260 | Moderate |
C. auris 4 | 0 | No activity | 0.787 | Weak | 0.692 | Weak | 0 | No activity | 0.208 | Moderate |
C. auris 5 | 0 | No activity | 0.804 | Weak | 0.755 | Weak | 0 | No activity | 0.228 | Moderate |
C. auris 6 | 0 | No activity | 0.792 | Weak | 0.720 | Weak | 0 | No activity | 0.261 | Moderate |
C. auris 7 | 0 | No activity | 0.833 | Weak | 0.723 | Weak | 0 | No activity | 0.276 | Moderate |
C. albicans ATCC 10231 | 0.350 | Strong | 0.412 | Strong | 0.500 | Strong | ND | ND | ND | ND |
C. albicans ATCC 90028 | ND | ND | ND | ND | ND | ND | 0.42 | Strong | 0.520 | Strong |
Media only | 0.097 | - |
Fluconazole | Amfoterisin | Kaspofungin | CSA-13 | CSA-44 | CSA-131 | CSA-138 | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
MIC | MBEC | MIC | MBEC | MIC | MBEC | MIC | MBEC | MIC | MBEC | MIC | MBEC | MIC | MBEC | |
C. auris 1 | >128 | ND | 1 | 160 | 0.06 | 160 | 8 | 1280 | 4 | 640 | 1 | 1280 | 1 | 640 |
C. auris 2 | >128 | ND | 1 | 320 | 0.125 | 160 | 8 | 1280 | 4 | 160 | 1 | 640 | 1 | 640 |
C. auris 3 | >128 | ND | 1 | 160 | 0.06 | 160 | 8 | 640 | 4 | 320 | 1 | 80 | 1 | 320 |
C. auris 4 | >128 | ND | 1 | 80 | 0.06 | 160 | 8 | 640 | 4 | 320 | 1 | 80 | 1 | 160 |
C. auris 5 | >128 | ND | 1 | 160 | 0.25 | 320 | 8 | 320 | 4 | 320 | 1 | 320 | 1 | 160 |
C. auris 6 | >128 | ND | 1 | 80 | 0.06 | 40 | 8 | 160 | 4 | 640 | 1 | 640 | 0.5 | 320 |
C. auris 7 | >128 | ND | 1 | 160 | 0.5 | 160 | 8 | 1280 | 4 | 640 | 1 | 160 | 0.5 | 640 |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Oyardi, O.; Demir, E.S.; Alkan, B.; Komec, S.; Genc, G.E.; Aygun, G.; Teke, L.; Turan, D.; Erturan, Z.; Savage, P.B.; et al. Phenotypic Investigation of Virulence Factors, Susceptibility to Ceragenins, and the Impact of Biofilm Formation on Drug Efficacy in Candida auris Isolates from Türkiye. J. Fungi 2023, 9, 1026. https://doi.org/10.3390/jof9101026
Oyardi O, Demir ES, Alkan B, Komec S, Genc GE, Aygun G, Teke L, Turan D, Erturan Z, Savage PB, et al. Phenotypic Investigation of Virulence Factors, Susceptibility to Ceragenins, and the Impact of Biofilm Formation on Drug Efficacy in Candida auris Isolates from Türkiye. Journal of Fungi. 2023; 9(10):1026. https://doi.org/10.3390/jof9101026
Chicago/Turabian StyleOyardi, Ozlem, Elif Sena Demir, Busra Alkan, Selda Komec, Gonca Erkose Genc, Gokhan Aygun, Leyla Teke, Deniz Turan, Zayre Erturan, Paul B. Savage, and et al. 2023. "Phenotypic Investigation of Virulence Factors, Susceptibility to Ceragenins, and the Impact of Biofilm Formation on Drug Efficacy in Candida auris Isolates from Türkiye" Journal of Fungi 9, no. 10: 1026. https://doi.org/10.3390/jof9101026