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<p><i>Aspergillus fumigatus</i> is a major opportunistic fungal pathogen and an important cause of invasive aspergillosis in immunocompromised patients. Azole antifungals remain central to treatment, but azole resistance is increasingly reported. Azole resistance in <i>A. fumigatus</i> is often linked to canonical <i>cyp51A </i>mechanisms, but many resistant isolates lack these mutations, suggesting additional contributions. This study analysed 12 newly sequenced azole-susceptible clinical isolates from KwaZulu-Natal, South Africa, together with publicly available clinical and environmental <i>A. fumigatus</i> genomes using a uniform AF293 reference-based workflow for variant calling, population structure correction and genome wide association studies (GWAS). A filtered SNP-alignment matrix was used to infer population structure and perform structure-aware genome-wide association testing with azole susceptibility status as a binary phenotype. Overall, 194 of 227 genomes met predefined quality thresholds, and 31 949 biallelic SNPs were tested using ten PCoA axes as covariates. After adjustment using SNP-derived PCoA covariates, 16 SNPs exceeded the Bonferroni threshold and 206 SNPs passed BH-FDR correction. The strongest association signals were distributed across multiple genomic regions rather than being restricted to a single canonical resistance locus, with candidate annotations linked to sterol and lipid metabolism, membrane transport, transcriptional regulation, cell-wall remodelling and stress response. Transporter-focused analysis showed that all 12 South African isolates had negative CDR1 and MFS transporter-balance scores, placing them among the most transporter-depleted susceptible backgrounds in the dataset. Phylogenetic reconstruction showed interspersed resistant and susceptible isolates, supporting repeated emergence or local amplification rather than expansion of a single resistant clone. Overall, these findings support a cautious model in which azole resistance-associated variation in <i>A. fumigatus</i> is distributed across multiple functional pathways within a structured population background. The South African isolates provide a local susceptible clinical baseline for future expanded surveillance.</p><p><b>Keywords</b>: <i>Aspergillus fumigatus,</i> Azole resistance, Genome Wide Association, SNPs</p>

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Genomic insights into azole resistance in Aspergillus fumigatus: findings from global and South African clinical isolates

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月3日

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  • Siphiwengesihle Kuhle Silindile Mbamali,
  • Nikwando Mohlomi,
  • Magriet van der Nest,
  • Nokuthula Peace Mchunu,
  • Kugen Permaul

摘要

Aspergillus fumigatus is a major opportunistic fungal pathogen and an important cause of invasive aspergillosis in immunocompromised patients. Azole antifungals remain central to treatment, but azole resistance is increasingly reported. Azole resistance in A. fumigatus is often linked to canonical cyp51A mechanisms, but many resistant isolates lack these mutations, suggesting additional contributions. This study analysed 12 newly sequenced azole-susceptible clinical isolates from KwaZulu-Natal, South Africa, together with publicly available clinical and environmental A. fumigatus genomes using a uniform AF293 reference-based workflow for variant calling, population structure correction and genome wide association studies (GWAS). A filtered SNP-alignment matrix was used to infer population structure and perform structure-aware genome-wide association testing with azole susceptibility status as a binary phenotype. Overall, 194 of 227 genomes met predefined quality thresholds, and 31 949 biallelic SNPs were tested using ten PCoA axes as covariates. After adjustment using SNP-derived PCoA covariates, 16 SNPs exceeded the Bonferroni threshold and 206 SNPs passed BH-FDR correction. The strongest association signals were distributed across multiple genomic regions rather than being restricted to a single canonical resistance locus, with candidate annotations linked to sterol and lipid metabolism, membrane transport, transcriptional regulation, cell-wall remodelling and stress response. Transporter-focused analysis showed that all 12 South African isolates had negative CDR1 and MFS transporter-balance scores, placing them among the most transporter-depleted susceptible backgrounds in the dataset. Phylogenetic reconstruction showed interspersed resistant and susceptible isolates, supporting repeated emergence or local amplification rather than expansion of a single resistant clone. Overall, these findings support a cautious model in which azole resistance-associated variation in A. fumigatus is distributed across multiple functional pathways within a structured population background. The South African isolates provide a local susceptible clinical baseline for future expanded surveillance.

Keywords: Aspergillus fumigatus, Azole resistance, Genome Wide Association, SNPs