Aspergillus fumigatuscan display persistence to the fungicidal drug voriconazole

Abstract

Aspergillus fumigatus is a filamentous fungus that can infect the lungs of patients with immunosuppression and/or underlying lung diseases. The mortality rates associated with chronic and invasive aspergillosis infections remain very high, despite availability of antifungal treatment. In the last decade, there has been a worrisome emergence and spread of resistance to the azole class of antifungals, which are the first line therapy for the treatment of A. fumigatus infections. The mortality caused by resistant isolates is even higher, and the management of these patients is complicated as the therapeutic options are severely reduced. Nevertheless, treatment failure is also common in patients infected with azole susceptible isolates, which can be due to several non-mutually exclusive reasons, such as poor drug absorption. In addition, the phenomena of tolerance or persistence, where susceptible pathogens have the ability to survive the action of an antimicrobial for extended periods of time, have been associated with treatment failure in bacterial infections, and their occurrence in fungal infections already proposed. Here, we investigated the A. fumigatus response to the azole voriconazole and demonstrate that certain isolates of this fungal pathogen can display persistence to this antifungal. A sub-population of the persister isolates can survive for extended periods and even grow at a slow rate in the presence of supra-MIC (minimum inhibitory concentration) of voriconazole. Persistence cannot be eradicated with adjuvant drugs or antifungal drug combinations and reduces the efficacy of treatment in a Galleria mellonella model of infection. Furthermore, persistence implies a distinct transcriptional profile, demonstrating that it is an active response to the drug. For all these reasons, we propose that azole persistence may be a relevant and underestimated factor that influences the outcome of infection in human aspergillosis.

Macrophage internalization creates a multidrug-tolerant fungal persister reservoir and facilitates the emergence of drug resistance

“…Our group, however, has characterized a small subpopulation of C. glabrata persisters in vitro (which we referred to as "drug-tolerant cells") surviving supra-high MIC concentration of echinocandins 27,28 . Such subpopulations growing or surviving supra-high MIC concentrations of static or cidal antifungal drugs, respectively, have been observed in multiple fungal species and proposed to be involved in therapeutic failure, emergence of resistance, and poor clinical outcomes [29][30][31][32] . As described above, bacterial persisters are induced by environmental stress and internalization by host immune cells.…”

Macrophage internalization creates a multidrug-tolerant fungal persister population, providing a permissive reservoir for the emergence of drug resistance

“…Our group, however, has characterized a small subpopulation of C. glabrata persisters in vitro (which we referred to as "drug-tolerant cells") surviving supra-high MIC concentration of echinocandins (15,28). Such subpopulations growing or surviving supra-high MIC concentrations of static or cidal antifungal drugs, respectively, have been observed in multiple fungal species and proposed to be involved in therapeutic failure, emergence of resistance, and poor clinical outcomes (29)(30)(31)(32).…”