1H, 13C, 15 N chemical shift assignments of the FKBP12 protein from the pathogenic fungi Candida auris and Candida glabrata

  • Qamar Bashir
  • David M. LeMaster
  • Griselda HernándezEmail author


Multi-drug resistance is becoming an increasingly severe clinical challenge not only among pathogenic bacteria but among fungal pathogens as well. Drug design is inherently more challenging for the eukaryotic fungi due to their closer evolutionary similarity to humans. The recent rapid expansion in invasive infections throughout the world by Candida auris is of particular concern due to a substantial mortality rate, comparatively facile transmission, and an increasing level of resistance to all three of the major classes of anti-fungal drugs. One promising avenue for the development of an alternative class of anti-fungal agents currently under investigation is for drugs against the FK506-binding protein FKBP12 which, when bound to that drug, inhibits the fungal calcineurin signaling pathway with a resultant diminution in virulence. The specific challenge to this approach is that the homologous human calcineurin pathway functions in controlling the tissue immunity response, so that drug selectivity for the fungal pathway must be designed. To facilitate such efforts, we report the nearly complete backbone and sidechain resonances for the FKBP12 proteins of both Candida auris and clinically significant Candida glabrata fungi.


FKBP12 Candida auris Candida glabrata Multi-drug resistance 



We acknowledge the use of the NMR facility at the Wadsworth Center. This work was supported in part by National Institutes of Health [GM 119152 to G.H.].

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. Blankenship JR, Wormley FL, Boyce MK, Schell WA, Filler SG (2003) Calcineurin is essential for Candida albicans survival in serum and virulence. Eukaryot Cell 2:422–430. CrossRefGoogle Scholar
  2. Borst A, Raimer MT, Warnock DW, Morrison CJ, Arthington-Skaggs BA (2005) Rapid acquisition of stable azole resistance by Candida glabrata isolates obtained before the clinical introduction of fluconazole. Antimicrob Agents Chemother 49:783–787. CrossRefGoogle Scholar
  3. Chen YL, Lehman VN, Lewit Y, Averette AF, Heitman J (2013) Calcineurin governs thermotolerance and virulence of Cryptococcus gatti. Genetics 3:527–539. CrossRefGoogle Scholar
  4. Forsberg K, Woodworth K, Walters M, Berkow EL, Jackson B, Chiller T, Vallabhaneni S (2019) Candida auris: the recent emergence of a multidrug-resistant fungal pathogen. Med Mycol 57:1–12. CrossRefGoogle Scholar
  5. Gobeil SMC, Bobay BG, Spicer LD, Venters RA (2019) 15N, 13C and 1H resonance assignments of FKBP12 proteins from the pathogenic fungi Mucor circinelloides and Aspergillus fumigatus. Biomol NMR Assign 13:207–212. CrossRefGoogle Scholar
  6. Juvvadi PR, Fox DI, Bobay BG, Hoy MJ, Gobeil SMC, Venters RA, Chang Z, Lin JJ, Averette AF, Cole C, Barrington BC, Wheaton JD, Ciofani M, Trzoss M, Li X, Lee SC, Chen YL, Mutz M, Spicer LD, Schumacher MA, Heitman J, Steinbach WJ (2019) Harnessing calcineurin-FK506-FKBP12 crystal structures from invasive fungal pathogens to develop antifungal agents. Nat Commun. CrossRefGoogle Scholar
  7. Kay LE, Xu GY, Singer AU, Muhandiram DR, Forman-Kay JD (1993) A gradient-enhanced HCCH TOCSY experiment for recording side-chain H-1 and C-13 correlations in H2O samples of proteins. J Magn Reson B 101:333–337. ADSCrossRefGoogle Scholar
  8. Kay LE, Xu GY, Yamazaki T (1994) Enhanced-sensitivity triple-resonance spectroscopy with minimal H2O saturation. J Magn Reson A 109:129–133. ADSCrossRefGoogle Scholar
  9. Lee WG, Shin JH, Uh Y (2011) First three reported cases of nosocomial fungemia caused by Candida auris. J Clin Microbiol 49:3139–3142. CrossRefGoogle Scholar
  10. Lockhart SR, Etienne KA, Vallabhaneni S, Farooqi J, Chowdhary A, Govender NP, Colombo AL, Calvo B, Cuomo CA, Desjardins CA, Berkow EL, Castanheira M, Magobo RE, Jabeen K, Asghar RJ, Meis JF, Jackson B, Chiller T, Litvintseva AP (2017) Simultaneous emergence of multidrug-resistant Candida auris on 3 continents confirmed by whole-genome sequencing and epidemiological analyses. Clin Infect Dis 64:134–140. CrossRefGoogle Scholar
  11. Lone SA, Ahmad A (2019) Candida auris—the growing menace to global health. Mycoses 62:620–637. CrossRefGoogle Scholar
  12. Muhandiram DR, Kay LE (1994) Gradient-enhanced triple-resonance three-dimensional NMR experiments with improved sensitivity. J Magn Reson B 103:203–216. CrossRefGoogle Scholar
  13. Mustafi SM, Chen H, Li H, Lemaster DM, Hernández G (2013) Analyzing the visible conformational substates of the FK506-binding protein FKBP12. Biochem J 453:371–380. CrossRefGoogle Scholar
  14. Odom A, Muir S, Lim E, Toffaletti DL, Perfect JR, Heitman J (1997) Calcineurin is required for virulence of Cryptococcus neoformans. EMBO J 16:2576–2589. CrossRefGoogle Scholar
  15. Pais P, Galocha M, Viana R, Cavalheiro M, Pereira D, Teixeira MC (2019) Microevolution of the pathogenic yeasts Candida albicans and Candida glabrata during antifungal therapy and host infection. Microbial Cell 6:142–159. CrossRefGoogle Scholar
  16. Palmer AG, Cavanagh J, Wright PE, Rance M (1991) Sensitivity improvement in proton-detected two-dimensional heteronuclear correlation NMR spectroscopy. J Magn Reson 93:151–170. ADSCrossRefGoogle Scholar
  17. Park HS, Lee SC, Cardenas ME, Heitman J (2019) Calcium-calmodulin-calcineurin signaling: a globally conserved virulence cascade in eukaryotic microbial pathogens. Cell Host Microbe 26:453–462. CrossRefGoogle Scholar
  18. Rhodes J, Fisher MC (2019) Global epidemiology of emerging Candida auris. Cuur Opin Microbiol 52:84–89. CrossRefGoogle Scholar
  19. Steinbach WJ, Cramer RA Jr, Perfect BZ, Asfaw YG, Sauer TC, Najvar LK, Kirkpatrick WR, Patterson TF, Benjamin DK Jr, Heitman J (2006) Calcineurin controls growth, morphology, ad pathogenicity in Aspergillus fumigatus. Eukaryot Cell 5:1091–1103. CrossRefGoogle Scholar
  20. Tonthat NK, Juvvadi PR, Zhang H, Lee SC, Venters R, Spicer L, Steinbach WJ, Heitman J, Schumacher MA (2016) Structures of pathogenic fungal fkbp12s reveal possible self-catalysis function. mBio 7:e00492–00416. CrossRefGoogle Scholar
  21. Vuister GW, Bax A (1992) Resolution enhancement and spectral editing of uniformily 13C-enriched proteins by homonuclear broadband 13C decoupling. J Magn Reson 98:428–435. ADSCrossRefGoogle Scholar
  22. Wishart DS, Bigam CG, Yao J, Abildgaard F, Dyson HJ, Oldfield E, Markley JL, Sykes BD (1995) 1H, 13C, and 15N chemical shift referencing in biomolecular NMR. J Biomol NMR 6:135–140. CrossRefGoogle Scholar
  23. Yamazaki T, Lee W, Arrowsmith CH, Muhandiram DR, Kay LE (1994) A suite of triple resonance NMR experiments for the backbone assignment of 15N, 13C, 2H labeled proteins with high sensitivity. J Am Chem Soc 116:11655–11666. CrossRefGoogle Scholar

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© Springer Nature B.V. 2020

Authors and Affiliations

  1. 1.Wadsworth CenterNew York State Department of HealthAlbanyUSA

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