J Lescar1, I Meyer2, K Akshita3, K Srinivasaraghavan4, C Verma5, M Palous2, D Mazier6, A Datry6, A Fekkar7. 1. School of Biological Sciences, Nanyang Technological University, Singapore Centre d'Immunologie et des Maladies Infectieuses, CIMI-Paris, F-75013 Paris, France. 2. AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Parasitologie Mycologie, F-75013 Paris, France. 3. School of Biological Sciences, Nanyang Technological University, Singapore. 4. Bioinformatics Institute AStar, 30 Biopolis Street, Singapore 138671. 5. School of Biological Sciences, Nanyang Technological University, Singapore Bioinformatics Institute AStar, 30 Biopolis Street, Singapore 138671 Department of Biological Sciences, National University of Singapore, Singapore. 6. Centre d'Immunologie et des Maladies Infectieuses, CIMI-Paris, F-75013 Paris, France AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Parasitologie Mycologie, F-75013 Paris, France Sorbonne Universités, UPMC Univ Paris 06, CIMI-Paris, F-75005 Paris, France. 7. Centre d'Immunologie et des Maladies Infectieuses, CIMI-Paris, F-75013 Paris, France AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Parasitologie Mycologie, F-75013 Paris, France Sorbonne Universités, UPMC Univ Paris 06, CIMI-Paris, F-75005 Paris, France arnaud.fekkar@psl.aphp.fr.
Abstract
OBJECTIVES: Voriconazole, itraconazole and posaconazole are members of the azole family and widely used for the treatment of aspergillosis. They act by inhibiting the activity of the fungal Cyp51A enzyme. The emergence of environmental azole-resistant Aspergillus fumigatus strains raises major concerns for human health. METHODS: Recently, a new cyp51A-mediated resistance mechanism (namely TR46/Y121F/T289A) was described in clinical samples and patient-frequented environmental sites. In an azole-naive patient, we isolated an A. fumigatus strain that was not susceptible to voriconazole but was susceptible to itraconazole and posaconazole. RESULTS: A molecular analysis indicated a single Y121F substitution without the TR46 or T289A alterations, which to our knowledge has never been reported. Structure modelling and molecular dynamics offered an explanation for the resistance profile consistent with the structural differences between the three azoles. CONCLUSIONS: Taken together, these observations suggest an original mechanism conferring resistance to azoles mediated by cyp51A of environmental origin. This uncommon susceptibility pattern might represent a 'missing link' between the wild-type A. fumigatus and the fully azole-resistant strain harbouring the TR46/Y121F/T289A mutations.
OBJECTIVES:Voriconazole, itraconazole and posaconazole are members of the azole family and widely used for the treatment of aspergillosis. They act by inhibiting the activity of the fungal Cyp51A enzyme. The emergence of environmental azole-resistant Aspergillus fumigatus strains raises major concerns for human health. METHODS: Recently, a new cyp51A-mediated resistance mechanism (namely TR46/Y121F/T289A) was described in clinical samples and patient-frequented environmental sites. In an azole-naive patient, we isolated an A. fumigatus strain that was not susceptible to voriconazole but was susceptible to itraconazole and posaconazole. RESULTS: A molecular analysis indicated a single Y121F substitution without the TR46 or T289A alterations, which to our knowledge has never been reported. Structure modelling and molecular dynamics offered an explanation for the resistance profile consistent with the structural differences between the three azoles. CONCLUSIONS: Taken together, these observations suggest an original mechanism conferring resistance to azoles mediated by cyp51A of environmental origin. This uncommon susceptibility pattern might represent a 'missing link' between the wild-type A. fumigatus and the fully azole-resistant strain harbouring the TR46/Y121F/T289A mutations.
Authors: Jacques F Meis; Anuradha Chowdhary; Johanna L Rhodes; Matthew C Fisher; Paul E Verweij Journal: Philos Trans R Soc Lond B Biol Sci Date: 2016-12-05 Impact factor: 6.237
Authors: S Imbert; M Palous; I Meyer; E Dannaoui; D Mazier; A Datry; A Fekkar Journal: Antimicrob Agents Chemother Date: 2014-09-08 Impact factor: 5.191
Authors: L Bernal-Martínez; H Gil; O Rivero-Menéndez; S Gago; M Cuenca-Estrella; E Mellado; A Alastruey-Izquierdo Journal: Antimicrob Agents Chemother Date: 2017-11-22 Impact factor: 5.191