Combination of the mutations in hmg1 and in cyp51A results in high-level triazole-resistance in Aspergillus fumigatus causing chronic cavitary pulmonary aspergillosis

Author:

Tianyu Lianga, Nir Osherovb, Ruoyu Lia, Qiqi Wanga, Wei Chena, Zhe Wana, Wei Liua*

Author address:

Department of Dermatology and Venerology, Peking University First Hospital, National Clinical Research Center for Skin and Immune Diseases, Research Center for Medical Mycology, Peking University, Beijing, China, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, Beijing, Chinaa.
Department of Clinical Microbiology and Immunology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israelb.

Abstract:

Objectives: From a patient with chronic cavitary pulmonary aspergillosis (CCPA) and bronchopulmonary fistula, we isolated a strain of Aspergillus fumigatus with high-level triazole resistance that harbouring the combined mutations in cyp51A (M263I) and hmg1 (E306K). To clarify the role of the combination of the mutations in hmg1 and in cyp51A in triazole-resistance of A. fumigatus is the major purpose of this report.
Methods: The triazole-resistant A. fumigatus isolate BMU11335 was isolated from the BALF of a CCPA patient who failed long-term VRC therapy. Antifungal susceptibility of this A. fumigatus strain was assayed by using the broth microdilution method (CLSI M38-A3). Then the mutations were Besides, several mutants of A. fumigatus, including that with mutations in cyp51A alone, in hmg1 alone, as well as in both hmg1 and cyp51A, were constructed by using Cas9-RNP editing method. Finally, antifungal susceptibility of these mutants and the isolate A. fumigatus BMU11335 to common antifungal drugs, such as ITC, VRC, POS, ISZ, and AMB, was assayed.
Results: The isolate of A. fumigatus BMU11335 showed high-level resistance to all triazoles tested (BMU11335; ITC MIC > 64 μg/ml, VRC MIC = 8 μg/ml, POS MIC = 4 μg/ml, ISZ MIC = 8 μg/ml). And a M263I substitution in Cyp51A and an E306K substitution in Hmg1 were identified, accounting for the high-level pan-triazole-resistance in A. fumigatus BMU11335 since neither the M263I substitution in Cyp51A alone resulting in VRC MIC = 4 μg/ml and POS MIC = 0.5 μg/ml nor the E306K substitution in Hmg1 alone resulting in VRC MIC = 4 μg/ml and POS MIC = 2 μg/ml, as reported previously in A. fumigatus. Therefore, the combination of resistance mutations in cyp51A (M263I) and hmg1 (E306K) increased the MICs of all triazoles tested in our isolate, together resulting in a high-level pan-triazole-resistance in A. fumigatus BMU11335. Because A. fumigatus BMU11335 (AMB MIC = 0.5 μg/ml) retained its susceptibility to AMB, he was successfully treated with inhalation of AMB deoxycholate for 3 days which along with VRC therapy for 5 days.
Conclusions: The combination of resistance mutations in cyp51A (M263I) and hmg1 (E306K) results in a high-level pan-triazole-resistance in A. fumigatus. Given being increasingly reported worldwide, it is necessary to highlight the clinical impact of hmg1 mutations or even combined with cyp51A mutations on triazole-resistance in A. fumigatus, especially on the outcome of antifungal therapy. In addition, further studies on the application of AMB in treating aspergillosis caused by triazole-resistant A. fumigatus are needed.

Conference Year: 2024

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