Mycoses · 2026
Reduced Activity of Triazole Antifungal Agents Against Aspergillus tubingensis From a Global Collection of Genomically-Characterized Aspergillus Section Nigri Clinical Isolates (2020-2023).
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Kimbrough John H, Winkler Marisa L, Karr Maura H, Ewald Jessica M, Castanheira Mariana
Аннотация
BACKGROUND: The black moulds comprising Aspergillus section Nigri are clinically important organisms causing aspergillosis and otomycosis; triazole (azole) antifungal agents represent the primary prophylaxis and treatment option for these infections. The cryptic nature of species within section Nigri presents challenges for routine identification methods, yet accurate speciation may reveal important and overlooked trends in species distribution and azole antifungal activity.
METHOD: We used whole genome sequencing and comparative genomics to speciate 135 clinical A. section Nigri isolates collected worldwide from 2020 to 2023 and broth microdilution susceptibility testing to assess antifungal agent activity.
RESULTS: A. welwitschiae (n = 61; 45.2%) and A. tubingensis (n = 51; 37.8%) were the primary species identified. A. tubingensis accounted for 87.9% (n = 29/33) of isolates producing azole MIC values above the CLSI-established A. niger epidemiological cutoff values (ECV). All azoles displayed high activity (≥ 93.7% wildtype [WT]) against A. welwitschiae and A. niger isolates; A. tubingensis isolates were broadly inhibited by posaconazole (100% WT). The frequency of A. tubingensis isolates with NWT phenotypes against ≥ 2 azoles and the modal MIC values for most agents increased over time; azole-NWT isolates were present across all regions. Comparisons of protein sequences of CYP51A and CYP51B, the molecular target of azole activity, revealed unique residues in A. tubingensis. However, most azole-NWT isolates across species lacked unique CYP51A/B alterations, suggesting mechanisms outside target site modification influence elevated azole MIC values in this section.
CONCLUSIONS: Our results demonstrate the utility of speciating clinically relevant organism groups to better understand the dynamics of antifungal agent activity and species distributions.
METHOD: We used whole genome sequencing and comparative genomics to speciate 135 clinical A. section Nigri isolates collected worldwide from 2020 to 2023 and broth microdilution susceptibility testing to assess antifungal agent activity.
RESULTS: A. welwitschiae (n = 61; 45.2%) and A. tubingensis (n = 51; 37.8%) were the primary species identified. A. tubingensis accounted for 87.9% (n = 29/33) of isolates producing azole MIC values above the CLSI-established A. niger epidemiological cutoff values (ECV). All azoles displayed high activity (≥ 93.7% wildtype [WT]) against A. welwitschiae and A. niger isolates; A. tubingensis isolates were broadly inhibited by posaconazole (100% WT). The frequency of A. tubingensis isolates with NWT phenotypes against ≥ 2 azoles and the modal MIC values for most agents increased over time; azole-NWT isolates were present across all regions. Comparisons of protein sequences of CYP51A and CYP51B, the molecular target of azole activity, revealed unique residues in A. tubingensis. However, most azole-NWT isolates across species lacked unique CYP51A/B alterations, suggesting mechanisms outside target site modification influence elevated azole MIC values in this section.
CONCLUSIONS: Our results demonstrate the utility of speciating clinically relevant organism groups to better understand the dynamics of antifungal agent activity and species distributions.