A Cyp51B Mutation Contributes to Azole Resistance in Aspergillus fumigatus

Area of Science:

• Medical Mycology
• Antifungal Resistance
• Molecular Biology

Background:

• Azole resistance in Aspergillus fumigatus is a growing global health concern, limiting treatment options for aspergillosis.
• Resistance mechanisms are often linked to modifications in the Cyp51A enzyme, a primary target for azole drugs.
• Emerging strains exhibit azole resistance without Cyp51A alterations, necessitating exploration of novel resistance mechanisms.

Purpose of the Study:

• To characterize the azole resistance mechanisms in two isogenic Aspergillus fumigatus clinical strains isolated from the same patient over time.
• To investigate the role of Cyp51B and Hmg1 mutations in conferring azole resistance in Aspergillus fumigatus.

Main Methods:

• Comparative analysis of two Aspergillus fumigatus clinical strains (CM8940 and CM9640) with differing azole resistance profiles.
• Genetic sequencing to identify mutations in key enzymes, including Cyp51A, Cyp51B, and Hmg1.
• Gene expression analysis to quantify the transcript levels of cyp51A, cyp51B, and hmg1.

Main Results:

• Both strains exhibited azole resistance but displayed distinct resistance mechanisms.
• Strain CM8940 possessed a known G54A mutation in Cyp51A.
• Strain CM9640 harbored a novel G457S mutation in Cyp51B and a F390L mutation in Hmg1, with higher gene expression of cyp51A, cyp51B, and hmg1 compared to CM8940.

Conclusions:

• Identified a novel azole resistance mechanism in Aspergillus fumigatus involving mutations in Cyp51B and Hmg1.
• Demonstrated that Aspergillus fumigatus can evolve distinct resistance mechanisms over time within the same patient.
• Highlighted the importance of investigating alternative targets and pathways beyond Cyp51A for understanding and combating azole resistance.