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Antimicrobial Agents and Chemotherapy, December 2006, p. 4018-4026, Vol. 50, No. 12
0066-4804/06/$08.00+0     doi:10.1128/AAC.00439-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Antifungal Effects on Metabolite Profiles of Medically Important Yeast Species Measured by Nuclear Magnetic Resonance Spectroscopy{triangledown}

Muireann Coen,1,{dagger} Jennifer Bodkin,1 Damla Power,3 William A. Bubb,1 Uwe Himmelreich,3,{ddagger} Philip W. Kuchel,1 and Tania C. Sorrell2,3*

School of Molecular and Microbial Biosciences, University of Sydney, Sydney, NSW 2006, Australia,1 Centre for Clinical Research Excellence in Infections and Bioethics in Haematological Malignancies, University of Sydney,2 Centre for Infectious Diseases and Microbiology and Westmead Millennium Institute, University of Sydney, Westmead, NSW 2145, Australia3

Received 7 April 2006/ Returned for modification 6 August 2006/ Accepted 8 September 2006

Drug-induced inhibition of fungal growth is used in the diagnostic laboratory to predict therapeutic efficacy but is relatively slow, and determination of endpoints can be problematic. Nuclear magnetic resonance (NMR) spectroscopy identifies the metabolic complement of microorganisms while monitoring utilization of constituents of the incubation medium. This technique may provide a rapid and objective indicator of antifungal effects. We evaluated the effects of caspofungin, amphotericin B (AMB), and voriconazole on metabolic profiles of yeast species cultured in RPMI-2% glucose-morpholinepropanesulfonic acid buffer in microtiter plates in a proof-of-principle study. 1H NMR spectra were obtained using Bruker NMR spectrometers at 1H frequencies of 600 and 360 MHz. Metabolites were identified by two-dimensional correlation NMR spectra, and relative peak integrals were calculated from one-dimensional 1H NMR spectra. MICs were determined by a modification of the Clinical and Laboratory Standards Institute broth microdilution method M27-A. Utilization of glucose and branched-chain and aromatic amino acid substrates was accompanied by fungal production of acetate, acetaldehyde, ethanol, formate, fumarate, glycerol, lactate, pyruvate, and succinate. Clear-cut metabolic endpoints indicating a greater than 50% reduction in substrate utilization and fungal metabolite production which correlated with MICs were noted at 16 and 24 h for all three drugs. At 8 h, reductions of greater than 50% for selected metabolites were noted for caspofungin and AMB. Direct NMR-based observation of metabolic alterations in yeast cultures reveals changes in key metabolic pathways and should be evaluated formally as a rapid technique for determining susceptibility to antifungal drugs.

* Corresponding author. Mailing address: Centre for Infectious Diseases and Microbiology, University of Sydney, Institute of Clinical Pathology and Medical Research, Level 3, Westmead Hospital, P.O. Box 533, Wentworthville NSW 2145, Australia. Phone: 61 2 9845 6012. Fax: 61 2 9891 5317. E-mail: tanias{at}icpmr.wsahs.nsw.gov.au.

{triangledown} Published ahead of print on 18 September 2006.

{dagger} Present address: Department Biomolecular Medicine, Faculty of Medicine, Imperial College London, United Kingdom.

{ddagger} Present address: Max Planck Institute for Neurological Research, Gleueler Str. 50, Cologne, Germany.

Antimicrobial Agents and Chemotherapy, December 2006, p. 4018-4026, Vol. 50, No. 12
0066-4804/06/$08.00+0     doi:10.1128/AAC.00439-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Plummer, R., Bodkin, J., Power, D., Pantarat, N., Bubb, W. A., Kuchel, P. W., Sorrell, T. C. (2007). Effect of Caspofungin on Metabolite Profiles of Aspergillus Species Determined by Nuclear Magnetic Resonance Spectroscopy. Antimicrob. Agents Chemother. 51: 4077-4084 [Abstract] [Full Text]  


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