Dataset Information


Screening and Characterization of a Non-cyp51A Mutation in an Aspergillus fumigatus cox10 Strain Conferring Azole Resistance.

ABSTRACT: The rapid and global emergence of azole resistance in the human pathogen Aspergillus fumigatus has drawn attention. Thus, a thorough understanding of its mechanisms of drug resistance requires extensive exploration. In this study, we found that the loss of the putative calcium-dependent protein-encoding gene algA causes an increased frequency of azole-resistant A. fumigatus isolates. In contrast to previously identified azole-resistant isolates related to cyp51A mutations, only one isolate carries a point mutation in cyp51A (F219L mutation) among 105 independent stable azole-resistant isolates. Through next-generation sequencing (NGS), we successfully identified a new mutation (R243Q substitution) conferring azole resistance in the putative A. fumigatus farnesyltransferase Cox10 (AfCox10) (AFUB_065450). High-performance liquid chromatography (HPLC) analysis verified that the decreased absorption of itraconazole in related Afcox10 mutants is the primary reason for itraconazole resistance. Moreover, a complementation experiment by reengineering the mutation in a parental wild-type background strain demonstrated that both the F219L and R243Q mutations contribute to itraconazole resistance in an algA-independent manner. These data collectively suggest that the loss of algA results in an increased frequency of azole-resistant isolates with a non-cyp51A mutation. Our findings indicate that there are many unexplored non-cyp51A mutations conferring azole resistance in A. fumigatus and that algA defects make it possible to isolate drug-resistant alleles. In addition, our study suggests that genome-wide sequencing combined with alignment comparison analysis is an efficient approach to identify the contribution of single nucleotide polymorphism (SNP) diversity to drug resistance.


PROVIDER: S-EPMC5192120 | BioStudies | 2017-01-01

REPOSITORIES: biostudies

Similar Datasets

2015-01-01 | S-EPMC4468671 | BioStudies
2020-01-01 | S-EPMC7178884 | BioStudies
2008-01-01 | S-EPMC2443929 | BioStudies
2018-01-01 | S-EPMC6308927 | BioStudies
2015-01-01 | S-EPMC4649140 | BioStudies
2009-01-01 | S-EPMC2744247 | BioStudies
2016-01-01 | S-EPMC4704245 | BioStudies
2019-01-01 | S-EPMC6811395 | BioStudies
2016-01-01 | S-EPMC4704222 | BioStudies
2010-01-01 | S-EPMC2876375 | BioStudies