Novel Point Mutations in cyp51A and cyp51B Genes Associated with Itraconazole and Posaconazole Resistance in Aspergillus clavatus Isolates

Research output: Contribution to journalArticle

  • External authors:
  • Mahdi Abastabar
  • Tahereh Hosseini
  • Reza Valadan
  • Milad Lagzian
  • Iman Haghani
  • Narges Aslani
  • Hamid Badali
  • Sadegh Nouripour-Sisakht
  • Mehdi Nazeri
  • Sara Gholami
  • Mahshid Vakili
  • Tahereh Shokohi
  • Mohammad T Hedayati

Abstract

Aspergillus clavatus is a common environmental species known to cause occupational allergic disease in grain handlers. We have recently observed azole-resistant isolates of this fungus as a cause of onychomycosis. To further characterize the cause of resistance, the genes encoding 14 α-sterol demethylase enzyme (cyp51A and cyp51B) were characterized and analyzed in 9 ITC-susceptible isolates and 6 isolates with high minimum inhibitory concentrations (MICs) of clinical (nail and sputum) and environmental A. clavatus strains. We found that six isolates with itraconazole MIC >16 mg/L demonstrated nonsynonymous mutations, including V51I, L378P, E483K, and E506G, and synonymous mutations, including F53F, A186A, Q276Q, and H359H. Moreover, P486S was detected in five strains with ITR MIC >16 mg/L. One mutation, F324S, was detected in an isolate with posaconazole MIC >16 mg/L. The effect of E483K and P486S mutations of CYP51A on azole resistance was further investigated using homology modeling and molecular dynamics. We found that E483K and P486S mutations were located near the ligand access channel of CYP51A that could partly lead to narrowing the entry of the ligand access channels. Therefore, we concluded that E483K and P486S mutations may potentially contribute to the limited access of inhibitors to the binding pocket and therefore confer resistance to azole agents.

Bibliographical metadata

Original languageEnglish
Pages (from-to)652-662
Number of pages11
JournalMicrobial drug resistance (Larchmont, N.Y.)
Volume25
Issue number5
Early online date30 May 2019
DOIs
Publication statusPublished - 1 Jun 2019