Abstract
Candida tropicalis is a human pathogen and one of the most prevalent non-Candida albicans Candida (NCAC) species causing invasive infections. Azole antifungal resistance in C. tropicalis is also gradually increasing with the increasing incidence of infections. The pathogenic success of C. tropicalis depends on its effective response in the host microenvironment. To become a successful pathogen, cellular metabolism, and physiological status determine the ability of the pathogen to counter diverse stresses inside the host. However, to date, limited knowledge is available on the impact of carbon substrate metabolism on stress adaptation and azole resistance in C. tropicalis. In this study, we determined the impact of glucose, fructose, and sucrose as the sole carbon source on the fluconazole resistance and osmotic (NaCl), oxidative (H2O2) stress adaptation in C. tropicalis clinical isolates. We confirmed that the abundance of carbon substrates influences or increases drug resistance and osmotic and oxidative stress tolerance in C. tropicalis. Additionally, both azole-resistant and susceptible isolates showed similar stress adaptation phenotypes, confirming the equal efficiency of becoming successful pathogens irrespective of drug susceptibility profile. To the best of our knowledge, our study is the first on C. tropicalis to demonstrate the direct relation between carbon substrate metabolism and stress tolerance or drug resistance.
Similar content being viewed by others
Data availability
No datasets were generated or analysed during the current study.
References
Al-Otibi F, Al-Zahrani RM, Marraiki N (2022) The crude oil biodegradation activity of Candida strains isolated from oil-reservoirs soils in Saudi Arabia. Sci Rep 12(1):10708. https://doi.org/10.1038/s41598-022-14836-0
Alves R, Barata-Antunes C, Casal M, Brown AJP, Van Dijck P, Paiva S (2020) Adapting to survive: how Candida overcomes host-imposed constraints during human colonization. PLoS Pathog 16(5):e1008478. https://doi.org/10.1371/journal.ppat.1008478
Arana DM, Alonso-Monge R, Du C, Calderone R, Pla J (2007) Differential susceptibility of mitogen-activated protein kinase pathway mutants to oxidative-mediated killing by phagocytes in the fungal pathogen Candida albicans. Cell Microbiol 9(7):1647–1659. https://doi.org/10.1111/j.1462-5822.2007.00898.x
Bastos AE, Moon DH, Rossi A, Trevors JT, Tsai SM (2000) Salt-tolerant phenol-degrading microorganisms isolated from amazonian soil samples. Arch Microbiol 174(5):346–352. https://doi.org/10.1007/s002030000216
Beales N (2004) Adaptation of microorganisms to Cold temperatures, weak acid preservatives, low pH, and osmotic stress: a review. Compr Rev Food Sci Food Saf 3(1):1–20. https://doi.org/10.1111/j.1541-4337.2004.tb00057.x
Brown AJ, Brown GD, Netea MG, Gow NA (2014) Metabolism impacts upon Candida immunogenicity and pathogenicity at multiple levels. Trends Microbiol 22(11):614–622. https://doi.org/10.1016/j.tim.2014.07.001
Brown AJ, Budge S, Kaloriti D, Tillmann A, Jacobsen MD, Yin Z, Ene IV, Bohovych I, Sandai D, Kastora S, Potrykus J, Ballou ER, Childers DS, Shahana S, Leach MD (2014b) Stress adaptation in a pathogenic fungus. J Exp Biol 217(Pt 1):144–155. https://doi.org/10.1242/jeb.088930
Butinar L, Santos S, Spencer-Martins I, Oren A, Gunde-Cimerman N (2005) Yeast diversity in hypersaline habitats. FEMS Microbiol Lett 244(2):229–234. https://doi.org/10.1016/j.femsle.2005.01.043
Chakrabarti A, Sood P, Rudramurthy SM, Chen S, Kaur H, Capoor M, Chhina D, Rao R, Eshwara VK, Xess I, Kindo AJ, Umabala P, Savio J, Patel A, Ray U, Mohan S, Iyer R, Chander J, Arora A, Mendiratta D (2015) Incidence, characteristics and outcome of ICU-acquired candidemia in India. Intensive Care Med 41(2):285–295. https://doi.org/10.1007/s00134-014-3603-2
Datta KK, Patil AH, Patel K, Dey G, Madugundu AK, Renuse S, Kaviyil JE, Sekhar R, Arunima A, Daswani B, Kaur I, Mohanty J, Sinha R, Jaiswal S, Sivapriya S, Sonnathi Y, Chattoo BB, Gowda H, Ravikumar R, Prasad TS (2016) Proteogenomics of Candida tropicalis–An Opportunistic Pathogen with Importance for Global Health. OMICS 20(4):239–247. https://doi.org/10.1089/omi.2015.0197
de Barros PP, Rossoni RD, Freire F, Ribeiro FC, Lopes L, Junqueira JC, Jorge AOC (2018) Candida tropicalis affects the virulence profile of Candida albicans: an in vitro and in vivo study. Pathog Dis 76(2). https://doi.org/10.1093/femspd/fty014
de Leon EM, Jacober SJ, Sobel JD, Foxman B (2002) Prevalence and risk factors for vaginal Candida colonization in women with type 1 and type 2 diabetes. BMC Infect Dis 2:1. https://doi.org/10.1186/1471-2334-2-1
Denning DW, Kneale M, Sobel JD, Rautemaa-Richardson R (2018) Global burden of recurrent vulvovaginal candidiasis: a systematic review. Lancet Infect Dis 18(11):e339–e347. https://doi.org/10.1016/S1473-3099(18)30103-8
Dos Santos MM, Ishida K (2023) We need to talk about Candida tropicalis: virulence factors and survival mechanisms. Med Mycol 61(8). https://doi.org/10.1093/mmy/myad075
Endalur Gopinarayanan V, Nair NU (2019) Pentose Metabolism in Saccharomyces cerevisiae: the need to engineer Global Regulatory systems. Biotechnol J 14(1):e1800364. https://doi.org/10.1002/biot.201800364
Ene IV, Adya AK, Wehmeier S, Brand AC, MacCallum DM, Gow NA, Brown AJ (2012) Host carbon sources modulate cell wall architecture, drug resistance and virulence in a fungal pathogen. Cell Microbiol 14(9):1319–1335. https://doi.org/10.1111/j.1462-5822.2012.01813.x
Fan X, Xiao M, Liao K, Kudinha T, Wang H, Zhang L, Hou X, Kong F, Xu YC (2017) Notable increasing Trend in Azole Non-susceptible Candida tropicalis Causing Invasive Candidiasis in China (August 2009 to July 2014): molecular epidemiology and clinical azole consumption. Front Microbiol 8:464. https://doi.org/10.3389/fmicb.2017.00464
Fisher MC, Denning DW (2023) The WHO fungal priority pathogens list as a game-changer. Nat Rev Microbiol 21(4):211–212. https://doi.org/10.1038/s41579-023-00861-x
Garcia MJ, Rios G, Ali R, Belles JM, Serrano R (1997) Comparative physiology of salt tolerance in Candida tropicalis and Saccharomyces cerevisiae. Microbiol (Reading) 143(4):1125–1131. https://doi.org/10.1099/00221287-143-4-1125
Garreau H, Hasan RN, Renault G, Estruch F, Boy-Marcotte E, Jacquet M (2000) Hyperphosphorylation of Msn2p and Msn4p in response to heat shock and the diauxic shift is inhibited by cAMP in Saccharomyces cerevisiae. Microbiol (Reading) 9146. https://doi.org/10.1099/00221287-146-9-2113
Gasch AP, Spellman PT, Kao CM, Carmel-Harel O, Eisen MB, Storz G, Botstein D, Brown PO (2000) Genomic expression programs in the response of yeast cells to environmental changes. Mol Biol Cell 11(12):4241–4257. https://doi.org/10.1091/mbc.11.12.4241
Ghosh AK, Paul S, Sood P, Rudramurthy SM, Rajbanshi A, Jillwin TJ, Chakrabarti A (2015) Matrix-assisted laser desorption ionization time-of-flight mass spectrometry for the rapid identification of yeasts causing bloodstream infections. Clin Microbiol Infect 21(4):372–378. https://doi.org/10.1016/j.cmi.2014.11.009
Hefny ZA, Ji B, Elsemman IE, Nielsen J, Van Dijck P (2024) Transcriptomic meta-analysis to identify potential antifungal targets in Candida albicans. BMC Microbiol 24(1):66. https://doi.org/10.1186/s12866-024-03213-8
Hirakawa MP, Martinez DA, Sakthikumar S, Anderson MZ, Berlin A, Gujja S, Zeng Q, Zisson E, Wang JM, Greenberg JM, Berman J, Bennett RJ, Cuomo CA (2015) Genetic and phenotypic intra-species variation in Candida albicans. Genome Res 25(3):413–425. https://doi.org/10.1101/gr.174623.114
Hu L, He C, Zhao C, Chen X, Hua H, Yan Z (2019) Characterization of oral candidiasis and the Candida species profile in patients with oral mucosal diseases. Microb Pathog 134:103575. https://doi.org/10.1016/j.micpath.2019.103575
Hui H, Huang D, McArthur D, Nissen N, Boros LG, Heaney AP (2009) Direct spectrophotometric determination of serum fructose in pancreatic cancer patients. Pancreas 38(6):706–712. https://doi.org/10.1097/MPA.0b013e3181a7c6e5
Kaltdorf M, Srivastava M, Gupta SK, Liang C, Binder J, Dietl AM, Meir Z, Haas H, Osherov N, Krappmann S, Dandekar T (2016) Systematic identification of anti-fungal drug targets by a Metabolic Network Approach. Front Mol Biosci 3:22. https://doi.org/10.3389/fmolb.2016.00022
Kawasaki T, Akanuma H, Yamanouchi T (2002) Increased fructose concentrations in blood and urine in patients with diabetes. Diabetes Care 25(2):353–357. https://doi.org/10.2337/diacare.25.2.353
Kwon SG, Park SW, Oh DK (2006) Increase of xylitol productivity by cell-recycle fermentation of Candida tropicalis using submerged membrane bioreactor. J Biosci Bioeng 101(1):13–18. https://doi.org/10.1263/jbb.101.13
Lao M, Li C, Li J, Chen D, Ding M, Gong Y (2020) Opportunistic invasive fungal disease in patients with type 2 diabetes mellitus from Southern China: clinical features and associated factors. J Diabetes Investig 11(3):731–744. https://doi.org/10.1111/jdi.13183
Lemaire K, Van de Velde S, Van Dijck P, Thevelein JM (2004) Glucose and sucrose act as agonist and mannose as antagonist ligands of the G protein-coupled receptor Gpr1 in the yeast Saccharomyces cerevisiae. Mol Cell 16(2):293–299. https://doi.org/10.1016/j.molcel.2004.10.004
Lortholary O, Renaudat C, Sitbon K, Desnos-Ollivier M, Bretagne S, Dromer F, Study FM, G (2017) The risk and clinical outcome of candidemia depending on underlying malignancy. Intensive Care Med 43(5):652–662. https://doi.org/10.1007/s00134-017-4743-y
Mandal SM, Mahata D, Migliolo L, Parekh A, Addy PS, Mandal M, Basak A (2014) Glucose directly promotes antifungal resistance in the fungal pathogen, Candida Spp. J Biol Chem 289(37):25468–25473. https://doi.org/10.1074/jbc.C114.571778
Martinez RF, Jaimes-Aveldanez A, Hernandez-Perez F, Arenas R, Miguel GF (2013) Oral Candida spp carriers: its prevalence in patients with type 2 diabetes mellitus. Bras Dermatol 88(2):222–225. https://doi.org/10.1590/S0365-05962013000200006
Mitchell A, Romano GH, Groisman B, Yona A, Dekel E, Kupiec M, Dahan O, Pilpel Y (2009) Adaptive prediction of environmental changes by microorganisms. Nature 460(7252):220–224. https://doi.org/10.1038/nature08112
Naseem S, Min K, Spitzer D, Gardin J, Konopka JB (2017) Regulation of Hyphal Growth and N-Acetylglucosamine catabolism by two transcription factors in Candida albicans. Genetics 206(1):299–314. https://doi.org/10.1534/genetics.117.201491
Nyirjesy P, Brookhart C, Lazenby G, Schwebke J, Sobel JD (2022) Vulvovaginal candidiasis: a review of the evidence for the 2021 Centers for Disease Control and Prevention of Sexually Transmitted Infections Treatment Guidelines. Clin Infect Dis 74(Suppl2):S162–S168. https://doi.org/10.1093/cid/ciab1057
Ou HT, Lee TY, Chen YC, Charbonneau C (2017) Pharmacoeconomic analysis of antifungal therapy for primary treatment of invasive candidiasis caused by Candida albicans and non-albicans Candida species. BMC Infect Dis 17(1):481. https://doi.org/10.1186/s12879-017-2573-8
Papon N, Naglik JR (2021) Candida Vaginitis: the importance of mitochondria and type I interferon signalling. Mucosal Immunol 14(5):975–977. https://doi.org/10.1038/s41385-021-00424-4
Patterson MJ, McKenzie CG, Smith DA, da Silva Dantas A, Sherston S, Veal EA, Morgan BA, MacCallum DM, Erwig LP, Quinn J (2013) Ybp1 and Gpx3 signaling in Candida albicans govern hydrogen peroxide-induced oxidation of the Cap1 transcription factor and macrophage escape. Antioxid Redox Signal 19(18):2244–2260. https://doi.org/10.1089/ars.2013.5199
Paul S, Singh S, Sharma D, Chakrabarti A, Rudramurthy SM, Ghosh AK (2020) Dynamics of in vitro development of azole resistance in Candida tropicalis. J Glob Antimicrob Resist 22:553–561. https://doi.org/10.1016/j.jgar.2020.04.018
Paul S, Dadwal R, Singh S, Shaw D, Chakrabarti A, Rudramurthy SM, Ghosh AK (2021) Rapid detection of ERG11 polymorphism associated azole resistance in Candida tropicalis. PLoS ONE 16(1):e0245160. https://doi.org/10.1371/journal.pone.0245160
Paul S, Shaw D, Joshi H, Singh S, Chakrabarti A, Rudramurthy SM, Ghosh AK (2022) Mechanisms of azole antifungal resistance in clinical isolates of Candida tropicalis. PLoS ONE 17(7):e0269721. https://doi.org/10.1371/journal.pone.0269721
Perlin DS, Rautemaa-Richardson R, Alastruey-Izquierdo A (2017) The global problem of antifungal resistance: prevalence, mechanisms, and management. Lancet Infect Dis 17(12):e383–e392. https://doi.org/10.1016/S1473-3099(17)30316-X
Ramsdale M, Selway L, Stead D, Walker J, Yin Z, Nicholls SM, Crowe J, Sheils EM, Brown AJ (2008) MNL1 regulates weak acid-induced stress responses of the fungal pathogen Candida albicans. Mol Biol Cell 19(10):4393–4403. https://doi.org/10.1091/mbc.e07-09-0946
Rocha MFG, Bandeira SP, de Alencar LP, Melo LM, Sales JA, Paiva MAN, Teixeira CEC, Castelo-Branco D, Pereira-Neto WA, Cordeiro RA, Sidrim JJC, Brilhante RSN (2017) Azole resistance in Candida albicans from animals: highlights on efflux pump activity and gene overexpression. Mycoses 60(7):462–468. https://doi.org/10.1111/myc.12611
Rodaki A, Bohovych IM, Enjalbert B, Young T, Odds FC, Gow NA, Brown AJ (2009) Glucose promotes stress resistance in the fungal pathogen Candida albicans. Mol Biol Cell 20(22):4845–4855. https://doi.org/10.1091/mbc.e09-01-0002
Rodrigues CF, Rodrigues ME, Henriques M (2019) Candida sp. Infections in patients with diabetes Mellitus. J Clin Med 8(1). https://doi.org/10.3390/jcm8010076
Roetzer A, Gregori C, Jennings AM, Quintin J, Ferrandon D, Butler G, Kuchler K, Ammerer G, Schuller C (2008) Candida Glabrata environmental stress response involves Saccharomyces cerevisiae Msn2/4 orthologous transcription factors. Mol Microbiol 69(3):603–620. https://doi.org/10.1111/j.1365-2958.2008.06301.x
Ruchala J, Sibirny AA (2021) Pentose metabolism and conversion to biofuels and high-value chemicals in yeasts. FEMS Microbiol Rev 45(4). https://doi.org/10.1093/femsre/fuaa069
Sabina J, Brown V (2009) Glucose sensing network in Candida albicans: a sweet spot for fungal morphogenesis. Eukaryot Cell 8(9):1314–1320. https://doi.org/10.1128/EC.00138-09
Suchodolski J, Krasowska A (2021) Fructose induces Fluconazole Resistance in Candida albicans through activation of Mdr1 and Cdr1 transporters. Int J Mol Sci 22(4). https://doi.org/10.3390/ijms22042127
Szczepaniak J, Lukaszewicz M, Krasowska A (2015) Estimation of Candida albicans ABC transporter behavior in real-time via fluorescence. Front Microbiol 6:1382. https://doi.org/10.3389/fmicb.2015.01382
Takhaveev V, Heinemann M (2018) Metabolic heterogeneity in clonal microbial populations. Curr Opin Microbiol 45:30–38. https://doi.org/10.1016/j.mib.2018.02.004
Van Ende M, Wijnants S, Van Dijck P (2019) Sugar Sensing and Signaling in Candida albicans and Candida Glabrata. Front Microbiol 10:99. https://doi.org/10.3389/fmicb.2019.00099
van Zyl C, Prior BA, Kilian SG, Brandt EV (1993) Role of D-ribose as a cometabolite in D-xylose metabolism by Saccharomyces cerevisiae. Appl Environ Microbiol 59(5):1487–1494. https://doi.org/10.1128/aem.59.5.1487-1494.1993
Viana R, Couceiro D, Carreiro T, Dias O, Rocha I, Teixeira MC (2022) A genome-scale metabolic model for the Human Pathogen Candida Parapsilosis and early identification of putative novel antifungal drug targets. Genes (Basel) 13(2). https://doi.org/10.3390/genes13020303
Wiederhold NP (2017) Antifungal resistance: current trends and future strategies to combat. Infect Drug Resist 10:249–259. https://doi.org/10.2147/IDR.S124918
Wijnants S, Vreys J, Van Dijck P (2022) Interesting antifungal drug targets in the central metabolism of Candida albicans. Trends Pharmacol Sci 43(1):69–79. https://doi.org/10.1016/j.tips.2021.10.003
Wisselink HW, Toirkens MJ, del Rosario Franco Berriel M, Winkler AA, van Dijken JP, Pronk JT, van Maris AJ (2007) Engineering of Saccharomyces cerevisiae for efficient anaerobic alcoholic fermentation of L-arabinose. Appl Environ Microbiol 73(15):4881–4891. https://doi.org/10.1128/AEM.00177-07
Wu PF, Liu WL, Hsieh MH, Hii IM, Lee YL, Lin YT, Ho MW, Liu CE, Chen YH, Wang FD (2017) Epidemiology and antifungal susceptibility of candidemia isolates of non-albicans Candida species from cancer patients. Emerg Microbes Infect 6(10):e87. https://doi.org/10.1038/emi.2017.74
Yeo IS, Cho BK, Kim JH (2021) Conversion of L-arabinose to L-ribose by genetically engineered Candida tropicalis. Bioprocess Biosyst Eng 44(6):1147–1154. https://doi.org/10.1007/s00449-020-02506-2
Young E, Poucher A, Comer A, Bailey A, Alper H (2011) Functional survey for heterologous sugar transport proteins, using Saccharomyces cerevisiae as a host. Appl Environ Microbiol 77(10):3311–3319. https://doi.org/10.1128/AEM.02651-10
Zuza-Alves DL, de Medeiros SS, de Souza LB, Silva-Rocha WP, Francisco EC, de Araujo MC, Lima-Neto RG, Neves RP, Melo AS, Chaves GM (2016) Evaluation of virulence factors in vitro, resistance to osmotic stress and Antifungal susceptibility of Candida tropicalis isolated from the Coastal Environment of Northeast Brazil. Front Microbiol 7:1783. https://doi.org/10.3389/fmicb.2016.01783
Zuza-Alves DL, Silva-Rocha WP, Chaves GM (2017) An Update on Candida tropicalis Based on Basic and Clinical Approaches. Front Microbiol, 8, 1927. https://doi.org/10.3389/fmicb.2017.01927
Funding
The authors duly acknowledge the Indian Council of Medical Research (ICMR), Government of India for financial supports.
Author information
Authors and Affiliations
Contributions
Arpita Khamrai and Saikat Paul are joint first authors for equal contribution to this manuscript.A.K & S.P. designed the study, conducted the experiments, acquired, analysed and interpreted the data and wrote the manuscript. S.M.R. revised it critically for important intellectual content. A.K.G. designed the study, analysed, and interpreted the results and revised it critically. All the authors have approved the final version of the article.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Communicated by Yusuf Akhter.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Khamrai, A., Paul, S., Rudramurthy, S.M. et al. Carbon substrates promotes stress resistance and drug tolerance in clinical isolates of Candida tropicalis. Arch Microbiol 206, 270 (2024). https://doi.org/10.1007/s00203-024-04000-9
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1007/s00203-024-04000-9