Sphingolipid Biosynthetic Pathway is Crucial for Growth, Biofilm Formation and Membrane Integrity of

Overview

Journal Future Med Chem

Specialties Chemistry
Pharmacy

Date 2019 Nov 13

PMID 31713454

Citations 11

Authors

Rodrigo Rollin-Pinheiro

Victor Pereira Rochetti

Mariana Ingrid Dutra da Silva Xisto

Livia Cristina Liporagi-Lopes

Beatriz Bastos

Antonella Rella

Ashutosh Singh

Sonia Rozental

Maurizio Del Poeta

Eliana Barreto-Bergter

Affiliations

Soon will be listed here.

Abstract

Glycosphingolipids are conserved lipids displaying a variety of functions in fungal cells, such as determination of cell polarity and virulence. They have been considered as potent targets for new antifungal drugs. The present work aimed to test two inhibitors, myriocin and DL-threo-1-Phenyl-2-palmitoylamino-3-morpholino-1-propanol, in , a pathogenic fungus which causes a wide range of disease. Mass spectrometry, microscopy and cell biology approaches showed that treatment with both inhibitors led to defects in fungal growth and membrane integrity, and caused an increased susceptibility to the current antifungal agents. These data demonstrate the antifungal potential of drugs inhibiting sphingolipid biosynthesis, as well as the usefulness of sphingolipids as promising targets for the development of new therapeutic options.

Citing Articles

Scedosporiosis and lomentosporiosis: modern perspectives on these difficult-to-treat rare mold infections.

Neoh C, Chen S, Lanternier F, Tio S, Halliday C, Kidd S Clin Microbiol Rev. 2024; 37(2):e0000423.

PMID: 38551323 PMC: 11237582. DOI: 10.1128/cmr.00004-23.

Structural and Functional Alterations Caused by Aureobasidin A in Clinical Resistant Strains of spp.

Rollin-Pinheiro R, de Moraes D, Bayona-Pacheco B, Curvelo J, Santos-Freitas G, Xisto M J Fungi (Basel). 2023; 9(11).

PMID: 37998920 PMC: 10672136. DOI: 10.3390/jof9111115.

Promising Antifungal Molecules against Mucormycosis Agents Identified from Pandemic Response Box: In Vitro and In Silico Analyses.

Xisto M, Rollin-Pinheiro R, Castro-Almeida Y, Santos-Freitas G, Rochetti V, Borba-Santos L J Fungi (Basel). 2023; 9(2).

PMID: 36836302 PMC: 9959553. DOI: 10.3390/jof9020187.

Pandemic Response Box® library as a source of antifungal drugs against Scedosporium and Lomentospora species.

Rollin-Pinheiro R, Xisto M, Castro-Almeida Y, Rochetti V, Borba-Santos L, da Silva Fontes Y PLoS One. 2023; 18(2):e0280964.

PMID: 36735743 PMC: 9897528. DOI: 10.1371/journal.pone.0280964.

Characterization of Biofilm Formation and Structure and Their Inhibition by Pea Defensin d2.

Correa-Almeida C, Borba-Santos L, Rollin-Pinheiro R, Barreto-Bergter E, Rozental S, Kurtenbach E Front Mol Biosci. 2022; 9:795255.

PMID: 35155575 PMC: 8830917. DOI: 10.3389/fmolb.2022.795255.

References

. EUCAST Technical Note on the method for the determination of broth dilution minimum inhibitory concentrations of antifungal agents for conidia-forming moulds. Clin Microbiol Infect. 2008; 14(10):982-4. DOI: 10.1111/j.1469-0691.2008.02086.x. View

Zhu C, Wang M, Wang W, Ruan R, Ma H, Mao C . Glucosylceramides are required for mycelial growth and full virulence in Penicillium digitatum. Biochem Biophys Res Commun. 2014; 455(3-4):165-71. PMC: 4380128. DOI: 10.1016/j.bbrc.2014.10.142. View

Lattif A, Mukherjee P, Chandra J, Roth M, Welti R, Rouabhia M . Lipidomics of Candida albicans biofilms reveals phase-dependent production of phospholipid molecular classes and role for lipid rafts in biofilm formation. Microbiology (Reading). 2011; 157(Pt 11):3232-3242. PMC: 3352276. DOI: 10.1099/mic.0.051086-0. View

da Silva A, Rodrigues M, Farias S, Almeida I, Pinto M, Barreto-Bergter E . Glucosylceramides in Colletotrichum gloeosporioides are involved in the differentiation of conidia into mycelial cells. FEBS Lett. 2004; 561(1-3):137-43. DOI: 10.1016/S0014-5793(04)00156-5. View

Thevissen K, Warnecke D, Francois I, Leipelt M, Heinz E, Ott C . Defensins from insects and plants interact with fungal glucosylceramides. J Biol Chem. 2003; 279(6):3900-5. DOI: 10.1074/jbc.M311165200. View

Oura T, Kajiwara S . Disruption of the sphingolipid Delta8-desaturase gene causes a delay in morphological changes in Candida albicans. Microbiology (Reading). 2008; 154(Pt 12):3795-3803. DOI: 10.1099/mic.0.2008/018788-0. View

Rollin-Pinheiro R, de Meirelles J, Vila T, Fonseca B, Alves V, Frases S . Biofilm Formation by Species: A Comparative Study. Front Microbiol. 2017; 8:1568. PMC: 5563321. DOI: 10.3389/fmicb.2017.01568. View

Taheri-Talesh N, Horio T, Araujo-Bazan L, Dou X, Espeso E, Penalva M . The tip growth apparatus of Aspergillus nidulans. Mol Biol Cell. 2008; 19(4):1439-49. PMC: 2291424. DOI: 10.1091/mbc.e07-05-0464. View

Rittershaus P, Kechichian T, Allegood J, Merrill Jr A, Hennig M, Luberto C . Glucosylceramide synthase is an essential regulator of pathogenicity of Cryptococcus neoformans. J Clin Invest. 2006; 116(6):1651-9. PMC: 1466548. DOI: 10.1172/JCI27890. View

10.

Li S, Du L, Yuen G, Harris S . Distinct ceramide synthases regulate polarized growth in the filamentous fungus Aspergillus nidulans. Mol Biol Cell. 2006; 17(3):1218-27. PMC: 1382311. DOI: 10.1091/mbc.e05-06-0533. View

11.

Rougeron A, Schuliar G, Leto J, Sitterle E, Landry D, Bougnoux M . Human-impacted areas of France are environmental reservoirs of the Pseudallescheria boydii/Scedosporium apiospermum species complex. Environ Microbiol. 2014; 17(4):1039-48. DOI: 10.1111/1462-2920.12472. View

12.

Perdoni F, Signorelli P, Cirasola D, Caretti A, Galimberti V, Biggiogera M . Antifungal activity of Myriocin on clinically relevant Aspergillus fumigatus strains producing biofilm. BMC Microbiol. 2015; 15:248. PMC: 4628231. DOI: 10.1186/s12866-015-0588-0. View

13.

de Melo N, Abdrahman A, Greig C, Mukherjee K, Thornton C, Ratcliffe N . Myriocin significantly increases the mortality of a non-mammalian model host during Candida pathogenesis. PLoS One. 2013; 8(11):e78905. PMC: 3829820. DOI: 10.1371/journal.pone.0078905. View

14.

Makushok T, Alves P, Huisman S, Kijowski A, Brunner D . Sterol-Rich Membrane Domains Define Fission Yeast Cell Polarity. Cell. 2016; 165(5):1182-1196. DOI: 10.1016/j.cell.2016.04.037. View

15.

Vila T, Chaturvedi A, Rozental S, Lopez-Ribot J . In Vitro Activity of Miltefosine against Candida albicans under Planktonic and Biofilm Growth Conditions and In Vivo Efficacy in a Murine Model of Oral Candidiasis. Antimicrob Agents Chemother. 2015; 59(12):7611-20. PMC: 4649157. DOI: 10.1128/AAC.01890-15. View

16.

Ramamoorthy V, Cahoon E, Thokala M, Kaur J, Li J, Shah D . Sphingolipid C-9 methyltransferases are important for growth and virulence but not for sensitivity to antifungal plant defensins in Fusarium graminearum. Eukaryot Cell. 2008; 8(2):217-29. PMC: 2643601. DOI: 10.1128/EC.00255-08. View

17.

Caretti A, Torelli R, Perdoni F, Falleni M, Tosi D, Zulueta A . Inhibition of ceramide de novo synthesis by myriocin produces the double effect of reducing pathological inflammation and exerting antifungal activity against A. fumigatus airways infection. Biochim Biophys Acta. 2016; 1860(6):1089-97. DOI: 10.1016/j.bbagen.2016.02.014. View

18.

BLIGH E, Dyer W . A rapid method of total lipid extraction and purification. Can J Biochem Physiol. 1959; 37(8):911-7. DOI: 10.1139/o59-099. View

19.

Pinto M, Rodrigues M, Travassos L, Haido R, Wait R, Barreto-Bergter E . Characterization of glucosylceramides in Pseudallescheria boydii and their involvement in fungal differentiation. Glycobiology. 2002; 12(4):251-60. DOI: 10.1093/glycob/12.4.251. View

20.

Tan H, Tay S . The inhibitory effects of aureobasidin A on Candida planktonic and biofilm cells. Mycoses. 2012; 56(2):150-6. DOI: 10.1111/j.1439-0507.2012.02225.x. View