de novo gtp biosynthesis is critical for virulence of the fungal pathogen cryptococcus neoformans更始三磷酸鸟苷生物合成是至关重要的真菌病原体的毒性新型隐球菌.pdf

De novo GTP Biosynthesis Is Critical for Virulence of the Fungal Pathogen Cryptococcus neoformans 1,2 2,3,4 2 1,2 1,2 2 Carl A. Morrow , Eugene Valkov , Anna Stamp , Eve W. L. Chow , I. Russel Lee , Ania Wronski , 1,2 2,5 6 1,2 1,2,4 Simon J. Williams , Justine M. Hill , Julianne T. Djordjevic , Ulrike Kappler , Bostjan Kobe , James A. Fraser1,2* 1 Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, Queensland, Australia, 2 School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland, Australia, 3 MRC Laboratory of Molecular Biology, Cambridge, United Kingdom, 4 Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia, 5 Centre for Advanced Imaging, University of Queensland, Brisbane, Queensland, Australia, 6 Centre for Infectious Diseases and Microbiology, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Sydney, New South Wales, Australia Abstract We have investigated the potential of the GTP synthesis pathways as chemotherapeutic targets in the human pathogen Cryptococcus neoformans, a common cause of fatal fungal meningoencephalitis. We find that de novo GTP biosynthesis, but not the alternate salvage pathway, is critical to cryptococcal dissemination and survival in vivo. Loss of inosine monophosphate dehydrogenase (IMPDH) in the de novo pathway results in slo