Novel antifungal activity of broxyquinoline against ITC-Resistant mutants via inhibition of methionine aminopeptidase in Aspergillus fumigatus - 15/09/25
, Siyuan Tao a, 1, Simin Xu a, Yangyang Yong d, Fei Gao a, Yuan Chen a, Chujie Lu a, Wei Lin b, c, ⁎ Highlights |
• | Broxyquinoline has fungicidal activity against various pathogenic Aspergillus and killed Aspergillus cells including itraconazole-resistant isolates at concentrations around the MIC. |
• | A synergistic combination of broxyquinoline and itraconazole was effective against ITC-resistant A. fumigatus. |
• | Broxyquinoline strongly inhibits the enzyme activity of AfMetAP. |
• | In vivo, overexpression of AfMetAP1 or AfMetAP2 antagonized broxyquinoline antifungal activity and rescued the cell growth. |
• | Broxyquinoline may inhibit the enzyme activity of AfMetAP through interacting with key residues T279A/W280A of AfMetAP1 and Y527A of AfMetAP2. |
Abstract |
Background |
A rising public health threat of invasive aspergillosis causing by azole-resistant Aspergillus species necessitates the development of novel antifungal agents. We performed a screening of antifungal compounds against azole-resistant fungi and broxyquinoline was identified. Our aim was to investigate its antifungal activities and antifungal mechanism.
Methods |
Fungal susceptibility testing for broxyquinoline carried out by the broth-based microdilution methods. Cell viability treated by broxyquinoline was tested by resazurin dye testing. The synergistic effect of broxyquinoline and itraconazole was evaluated using checkboard assay. Enzyme activity was investigated with spectrophotometric methods. The key amino acid residues in the binding of broxyquinoline with A. fumigatus methionine aminopeptidase (AfMetAP) were indicated by structural analyses, site-directed mutagenesis, and microscale thermophoresis (MST) assays.
Results |
Broxyquinoline has fungicidal activity against azole-resistant A. fumigatus and synergistic effects with itraconazole. Moreover, we discovered that broxyquinoline is strong inhibitor of AfMetAP through interacting with key residues T279A/W280A of AfMetAP1 and Y527A of AfMetAP2, and in vivo, the strains with high expression of AfMetAP are resistant to BQ.
Conclusions |
Broxyquinoline has antifungal activities against azole-resistant Aspergillus spp. and is also a potentiator of ITC in vitro. AfMetAP may biologically targets to BQ in vivo regulating antifungal activity. T279A/W280A of AfMetAP1 and Y527A of AfMetAP2 are key amino acid sites to maintain stable interactions between broxyquinoline and target enzymes AfMetAP.
Le texte complet de cet article est disponible en PDF.Keywords : Aspergillus spp., Antifungal, Broxyquinoline, Methionine aminopeptidase
Plan
Vol 35 - N° 4
Article 101577- décembre 2025 Retour au numéro
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