In vitro-in vivo correlation of voriconazole resistance due to G448S mutation (cyp51A gene) in Aspergillus fumigatus.
Invasive pulmonary aspergillosis continues to be associated with a high mortality despite timely and appropriate therapy. Although host immunity plays a major role in poor clinical response, antifungal drug resistance cannot be ignored. Our studies were aimed 1) to study the mechanism of drug resistance in voriconazole strains of Aspergillus fumigatus, 2) to establish a causal relationship between cyp51A mutation and voriconazole resistance (VRC-R), and 3) to determine whether VRC-R due to cyp51A mutation correlated with in vivo resistance. A point mutation (G448S) involving cyp51A gene in VRC-R isolate was associated with resistance to VRC but not to posaconazole (POS); POS had superior activity to VRC in reducing lung fungal burden and mortality in mice infected with a VRC-R mutant of A. fumigatus. Our study demonstrated that azole resistance is based on specific site of cyp51A mutation and that in vitro VRC-R correlates with in vivo resistance.
John D. Dingell VA Medical Center, Detroit, MI, USA. skrishn@med.wayne.edu
S
S
Krishnan Natesan
Wenjuan
W
Wu
J L
JL
Cutright
P H
PH
Chandrasekar
D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001232:Aspergillus fumigatus / Q000187:drug effects* / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004195:Disease Models, Animal; D025141:Drug Resistance, Fungal; D005260:Female; D005656:Fungal Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D020125:Mutation, Missense; D055732:Pulmonary Aspergillosis / Q000188:drug therapy* / Q000382:microbiology; D011743:Pyrimidines / Q000008:administration & dosage* / Q000494:pharmacology; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage* / Q000494:pharmacology; D065819:Voriconazole
D000935:Antifungal Agents; D005656:Fungal Proteins; D011743:Pyrimidines; D014230:Triazoles; C101425:posaconazole; D003577:Cytochrome P-450 Enzyme System; C465526:cytochrome P-450 CYP51A, Aspergillus; D065819:Voriconazole