Insights into the Multi-Azole Resistance Profile in Candida haemulonii Species Complex

Area of Science:

• Medical Mycology
• Antimicrobial Resistance
• Molecular Biology

Background:

• The Candida haemulonii complex comprises emerging opportunistic fungal pathogens causing invasive infections.
• This complex exhibits resistance to common antifungals like fluconazole, leading to treatment failures.

Purpose of the Study:

• To investigate the mechanisms of azole antifungal resistance in Brazilian clinical isolates of the Candida haemulonii complex.
• To determine the role of drug efflux pumps and ERG11 gene mutations in azole resistance.

Main Methods:

• Antifungal susceptibility testing and rhodamine-6G efflux assays were performed on 12 Candida haemulonii complex isolates.
• Efflux pump inhibitors (Phe-Arg, FK506) were used to assess their impact on resistance phenotypes.
• Gene expression analysis of efflux pumps (ChCDR1, ChCDR2, ChMDR1) and ERG11, along with ERG11 gene sequencing, were conducted.

Main Results:

• Nearly all isolates (91.7%) displayed azole cross-resistance.
• The Candida haemulonii complex showed significantly higher rhodamine-6G efflux compared to other non-albicans Candida species.
• Efflux pump inhibitors reversed fluconazole and voriconazole resistance.
• No significant modulation of efflux pump or ERG11 gene expression was observed with azole treatment.
• ERG11 gene sequencing identified mutations, some leading to amino acid polymorphisms.

Conclusions:

• Drug efflux pumps play a significant role in mediating azole resistance in the Candida haemulonii complex.
• Mutations in the ERG11 gene may also contribute to the observed azole resistance profile.
• Understanding these mechanisms is crucial for developing effective therapeutic strategies against these challenging infections.