Aspergillus fumigatus Can Display Persistence to the Fungicidal Drug Voriconazole

Abstract

The phenomena of antibacterial tolerance and persistence, where pathogenic microbes can survive for extended periods in the presence of cidal drug concentrations, have received significant attention in the last decade. Several mechanisms of action have been elucidated, and their relevance for treatment failure in bacterial infections demonstrated.

WITHDRAWN: Reversing olorofim activity reveals multifactorial drug tolerance in Aspergillus fumigatus

“…Worryingly, mortality from invasive infecDons with azole-resistant A. fumigatus approaches 100% and, in paDents with azole-resistant chronic infecDons anDfungal treatment is replaced by other medicaDons that are either poorly tolerated or less efficacious [12,13]. Lately, we have demonstrated that A. fumigatus shows persistence to the first-line anDfungal voriconazole exhibiDng low-rate growth at supra-inhibitory drug concentraDons [6].…”

“…Both responses have been linked to the emergence of anDbioDc resistance in bacteria, as a higher number of viable cells are available for the occurrence of resistance-conferring mutaDons during treatment [2]. Regardless tolerance and persistence are relaDvely new concepts in the fungal clinical research community, they have been already associated with treatment failure and the emergence of anDfungal resistance in yeasts [3,4] and are being increasingly recognised in filamentous fungi [5][6][7][8].…”

First Report of Azole-Resistant Aspergillus fumigatus with TR46/Y121F/T289A Mutations in Kuwait and an Update on Their Occurrence in the Middle East

“…Azole-resistant A. fumigatus isolates harboring nonsynonymous mutations in cyp51A have been recovered from patients with prolonged azole exposure and failing therapy [ 22 , 23 , 24 ]. Resistance-conferring mutations comprising tandem repeats (TR) in the promotor region and nonsynonymous mutation(s) in cyp51A linked primarily to environmental use of azoles in agriculture have also been detected in A. fumigatus isolates from azole-naïve patients [ 27 , 28 , 29 , 30 ]. Cyp51A mutations generally affect the susceptibility of A. fumigatus to all triazoles; however, the TR 34 /L98H mutation confers high-level resistance to itraconazole, while isolates with the TR 46 /Y121F/T289A mutation are highly resistant to voriconazole [ 7 , 27 , 30 , 31 ].…”

“…Resistance-conferring mutations comprising tandem repeats (TR) in the promotor region and nonsynonymous mutation(s) in cyp51A linked primarily to environmental use of azoles in agriculture have also been detected in A. fumigatus isolates from azole-naïve patients [ 27 , 28 , 29 , 30 ]. Cyp51A mutations generally affect the susceptibility of A. fumigatus to all triazoles; however, the TR 34 /L98H mutation confers high-level resistance to itraconazole, while isolates with the TR 46 /Y121F/T289A mutation are highly resistant to voriconazole [ 7 , 27 , 30 , 31 ]. The TR 34 /L98H mutation in Cyp51A in A. fumigatus is distributed worldwide, while the TR 46 /Y121F/T289A mutation is an emerging mechanism detected mostly in some European and Asian countries [ 27 , 30 ].…”

“…Cyp51A mutations generally affect the susceptibility of A. fumigatus to all triazoles; however, the TR 34 /L98H mutation confers high-level resistance to itraconazole, while isolates with the TR 46 /Y121F/T289A mutation are highly resistant to voriconazole [ 7 , 27 , 30 , 31 ]. The TR 34 /L98H mutation in Cyp51A in A. fumigatus is distributed worldwide, while the TR 46 /Y121F/T289A mutation is an emerging mechanism detected mostly in some European and Asian countries [ 27 , 30 ]. Although >130 clinical and environmental A. fumigatus isolates collected from 2008 to 2012 were screened, cyp51A TR 46 /Y121F/T289A mutants were not detected in our previous studies from Kuwait [ 28 , 31 , 32 ].…”