Disruption of de novo adenosine triphosphate (ATP) biosynthesis abolishes virulence in cryptococcus neoformans

Ross D. Blundell, Simon J. Williams, Samantha D.M. Arras, Jessica L. Chitty, Kirsten L. Blake, Daniel J. Ericsson, Nidhi Tibrewal, Jurgen Rohr, Y. Q.Andre E. Koh, Ulrike Kappler, Avril B. Robertson, Mark S. Butler, Matthew A. Cooper, Bostjan Kobe, James A. Fraser

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Opportunistic fungal pathogens such as Cryptococcus neoformans are a growing cause of morbidity and mortality among immunocompromised populations worldwide. To address the current paucity of antifungal therapeutic agents, further research into fungalspecific drug targets is required. Adenylosuccinate synthetase (AdSS) is a crucial enzyme in the adeosine triphosphate (ATP) biosynthetic pathway, catalyzing the formation of adenylosuccinate from inosine monophosphate and aspartate. We have investigated the potential of this enzyme as an antifungal drug target, finding that loss of function results in adenine auxotrophy in C. neoformans, as well as complete loss of virulence in a murine model. Cryptococcal AdSS was expressed and purified in Escherichia coli and the enzyme's crystal structure determined, the first example of a structure of this enzyme from fungi. Together with enzyme kinetic studies, this structural information enabled comparison of the fungal enzyme with the human orthologue and revealed species-specific differences potentially exploitable via rational drug design. These results validate AdSS as a promising antifungal drug target and lay a foundation for future in silico and in vitro screens for novel antifungal compounds.

Original languageEnglish
Pages (from-to)651-663
Number of pages13
JournalACS Infectious Diseases
Volume2
Issue number9
DOIs
StatePublished - Aug 9 2016

Bibliographical note

Funding Information:
National Health and Medical Research Council, Grant APP1049716.

Publisher Copyright:
© 2016 American Chemical Society.

Keywords

  • Antifungal
  • Cryptococcus Neoformans
  • Molecular Genetics
  • Target Verification
  • X-Ray Crystallography

ASJC Scopus subject areas

  • Infectious Diseases

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