Abstract:
:Invasive and allergic infections by Aspergillus flavus are more common in tropical and subtropical countries. The emergence of voriconazole (VRC) resistance in A. flavus impacts the management of aspergillosis, as azoles are used as the first-line and empirical therapy. We screened 120 molecularly confirmed A. flavus isolates obtained from respiratory and sinonasal specimens in a chest hospital in Delhi, India, for azole resistance using the CLSI broth microdilution (CLSI-BMD) method. Overall, 2.5% (n = 3/120) of A. flavus isolates had VRC MICs above epidemiological cutoff values (>1 μg/ml). The whole-genome sequence analysis of three non-wild-type (WT) A. flavus isolates with high VRC MICs showed polymorphisms in azole target genes (cyp51A, cyp51B, and cyp51C). Further, four novel substitutions (S196F, A324P, N423D, and V465M) encoded in the cyp51C gene were found in a single non-WT isolate which also exhibited overexpression of cyp51 (cyp51A, -B, and -C) genes and transporter genes, namely, MDR1, MDR2, atrF, and mfs1 The homology model of the non-WT isolate suggests that substitutions S196F and N423D exhibited major structural and functional effects on cyp51C drug binding. The substrate (drug) may not be able to bind to binding pocket due to changes in the pocket size or closing down or narrowing of cavities in drug entry channels. Notably, the remaining two VRC-resistant A. flavus isolates, including the one which had a pan-azole resistance phenotype (itraconazole and posaconazole), did not show upregulation of any of the analyzed target genes. These results suggest that multiple target genes and mechanisms could simultaneously contribute to azole resistance in A. flavus.
journal_name
Antimicrob Agents Chemotherjournal_title
Antimicrobial agents and chemotherapyauthors
Sharma C,Kumar R,Kumar N,Masih A,Gupta D,Chowdhary Adoi
10.1128/AAC.01928-17subject
Has Abstractpub_date
2018-02-23 00:00:00issue
3eissn
0066-4804issn
1098-6596pii
AAC.01928-17journal_volume
62pub_type
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journal_title:Antimicrobial agents and chemotherapy
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journal_title:Antimicrobial agents and chemotherapy
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journal_title:Antimicrobial agents and chemotherapy
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journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
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journal_title:Antimicrobial agents and chemotherapy
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journal_title:Antimicrobial agents and chemotherapy
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更新日期:1992-01-01 00:00:00
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journal_title:Antimicrobial agents and chemotherapy
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