Discovery of a novel azole-resistance mutation in Aspergillus fumigatus and the possible role of sexual reproduction in its evolution

J. Zhanga, Bas Zwaana, E Sneldersa, S Schoustraa, K Dijkb, J Meisc,d, F Hagenc,d, E Kuijpere, G Kampingaf, J Zolld,g, W Melchersd,g, P Verweijd,g and A Debetsa

Author address: 

aLaboratory of Genetics, Wageningen University, Wageningen, NL bDepartment of Medical Microbiology, Vu University Medical Centre, Amsterdam, The Netherlands cDepartment of Medical Microbiology and Infectious Diseases, CWZ Hospital, Nijmegen, The Netherlands dExpert Centre in Mycology Radboudumc/CWZ (EMRC) eDepartment of Medical Microbiology, Leiden University Medical Centre, Leiden, The Netherlands fDepartment of Medical Microbiology, University Medical Centre Groningen, Groningen, The Netherlands gDepartment of Medical Microbiology, Radboud University Medical Centre, Nijmegen, The Netherlands

Abstract: 

We investigated two compost-heaps, one containing azoles and one without azoles, for the presence of azole-resistant and azole-sensitive A. fumigatus isolates. The azole-free compost yielded 98% (49/50) sensitive and 2% (1/50) azole resistant isolates, whereas the azole-containing compost yielded 8% (4/45) sensitive and 92% (41/45) resistant isolates. From the latter, 84% (37/45) were of the highly resistant TR46 Y121F/ T289A genotype and 8% (4/45) had a novel pan–triazole-resistance harbouring a triple tandem repeat: TR46 3/Y121F/ M172I/T289A/G448S. The stark contrast between the two composts indicates that azole–containing compost is a hot spot for the development and maintenance of azole resistance. Subsequent screening of the clinical A. fumigatus collection from the Dutch national surveillance programme indicated that this resistance mechanism was already present in 2012, and is now found in all participating medical centres. We were able to recover this novel TR46 3 mutation among the sexual progeny in the lab, from a cross between two TR46 isolates of opposite mating type that were from the same compost. This strongly indicates a role of sex in the emergence of this novel azole–resistance mechanism in A. fumigatus. Furthermore, we provide further evidence indicating the potential occurrence of sexual reproduction in compost, but this still needs further confirmation. Our findings alarm the fast development of the azole resistance issue in A. fumigatus and further indicate the role of sexual reproduction of A. fumigatus in the development of azole resistance.

2017

abstract No: 

82

Full conference title: 

The Fourteenth International Aspergillus Meeting, Asilomar Conference Center, Pacific Grove, CA, USA
    • Asperfest 14 (2017)